1
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Jungfleisch J, Gebauer F. RNA-binding proteins as therapeutic targets in cancer. RNA Biol 2025; 22:1-8. [PMID: 40016176 PMCID: PMC11869776 DOI: 10.1080/15476286.2025.2470511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/04/2025] [Accepted: 02/17/2025] [Indexed: 03/01/2025] Open
Abstract
RNA-binding proteins (RBPs) have emerged as critical regulators of cancer progression, influencing virtually all hallmarks of cancer. Their ability to modulate gene expression patterns that promote or inhibit tumorigenesis has positioned RBPs as promising targets for novel anti-cancer therapies. This mini-review summarizes the current state of RBP-targeted cancer treatments, focusing on five examples, eIF4F, FTO, SF3B1, RBM39 and nucleolin. We highlight the diversity of current targeting approaches and discuss ongoing challenges including the complexity of RBP regulatory networks, potential off-target effects and the need for more specific targeting methods. By assessing the future potential of novel therapeutic avenues, we provide insights into the evolving landscape of cancer treatment and the critical role RBPs may play in next-generation therapeutics.
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Affiliation(s)
- Jennifer Jungfleisch
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Fátima Gebauer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
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2
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Prakash K, Satishkartik S, Ramalingam S, Gangadaran P, Gnanavel S, Aruljothi KN. Investigating the multifaceted role of nucleolin in cellular function and Cancer: Structure, Regulation, and therapeutic implications. Gene 2025; 957:149479. [PMID: 40210024 DOI: 10.1016/j.gene.2025.149479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/20/2025] [Accepted: 04/05/2025] [Indexed: 04/12/2025]
Abstract
Nucleolin (NCL), a highly conserved and multifunctional phosphoprotein, is primarily localized in the nucleolus and participates in various cellular compartments, including the nucleoplasm, cytoplasm, and plasma membrane. Initially discovered in the 1970 s, NCL is integral to ribosome biogenesis through its roles in ribosomal RNA transcription, processing, and assembly. Beyond ribosome synthesis, NCL plays critical roles in cellular processes such as DNA and RNA metabolism, chromatin remodeling, and cell cycle regulation, underscoring its essentiality for cell viability. Structurally, NCL comprises multiple functional domains, which facilitates interaction with various kinases and other proteins. NCL's extensive post-translational modifications influence its localization and function. Importantly, NCL has emerged as a key player in multiple pathologies, particularly cancer, where it contributes to tumor growth, metastasis, and drug resistance. On the cell surface, NCL acts as a co-receptor for growth factors and other ligands, facilitating oncogenic signaling. Additionally, its regulation of non-coding RNAs, stabilization of oncogenic mRNAs, and involvement in immune evasion highlight its potential as a therapeutic target. This review provides an unexplored in-depth overview of NCL's structure, functions, and modifications, with a focus on its role in cancer biology and its therapeutic implications.
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Affiliation(s)
- Kruthika Prakash
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India
| | - Srisri Satishkartik
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India
| | - Satish Ramalingam
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - S Gnanavel
- Biomaterials Laboratory, Department of Biomedical Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
| | - K N Aruljothi
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India.
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3
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Lopes-Nunes J, Lopes M, Rosado B, Maocha IG, Rolo J, Gaspar C, Pires B, Rosado T, Gallardo E, Palmeira-de-Oliveira A, Martinez-de-Oliveira J, Ferreira C, Cabral Campello MP, Paulo A, Medeiros-Fonseca B, Félix L, Venâncio C, Pinto MDL, Oliveira PA, Palmeira-de-Oliveira R, Cruz C. Vaginal formulation development: A strategy based on aptamer-guided liposome for human papillomavirus-induced lesions. Eur J Pharm Biopharm 2025; 210:114693. [PMID: 40154893 DOI: 10.1016/j.ejpb.2025.114693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 12/29/2024] [Accepted: 03/10/2025] [Indexed: 04/01/2025]
Abstract
Human Papillomavirus (HPV) is the main cause of cervical cancer, and formulations have been widely used to treat vaginal lesions caused by HPV. Herein, liposomes with acridine orange derivative C8 were produced and functionalized with AT11 aptamer. Subsequently, they were incorporated into a formulation, prepared based on the universal placebo formulation, which included Thymus vulgaris (TEO) or Origanum vulgare (OEO) essential oils. The formulation was technologically characterized and permeation of C8 into vaginal tissue was determined. To assess its biological effect, cell viability and internalization tests were carried out using the MTT assay and confocal microscopy, respectively, and antimicrobial susceptibility was also assessed. The prepared formulations were able to internalize cells and reduce cell viability, especially in cancer cell lines. Additionally, formulations showed promising antibacterial and antifungal effects. The effect of the formulation containing TEO and the C8 AT11 liposomes was also tested in vivo in HPV16 transgenic and wild type mice. Briefly, the formulation proved to be safe for animals and presented some therapeutic potential, namely through the reduction of ear epithelial cells' proliferation. Overall, results suggest that essential oils can increase the anticancer potential of liposomes with associated C8 and AT11 promotes their selectivity towards cancer cells.
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Affiliation(s)
- Jéssica Lopes-Nunes
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Melanie Lopes
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Beatriz Rosado
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Izamara Gomes Maocha
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Joana Rolo
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; Labfit-Health Products Research and Development Lda, UBImedical, Estrada Nacional 506, 6200-284 Covilhã, Portugal
| | - Carlos Gaspar
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Bruno Pires
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Tiago Rosado
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Eugénia Gallardo
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Ana Palmeira-de-Oliveira
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; Labfit-Health Products Research and Development Lda, UBImedical, Estrada Nacional 506, 6200-284 Covilhã, Portugal; Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - José Martinez-de-Oliveira
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Catarina Ferreira
- Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Maria Paula Cabral Campello
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, Portugal; Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, Portugal
| | - António Paulo
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, Portugal; Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, Portugal
| | - Beatriz Medeiros-Fonseca
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Luís Félix
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Carlos Venâncio
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Maria de Lurdes Pinto
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Paula A Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Rita Palmeira-de-Oliveira
- RISE-Health, Departamento de Ciências Médicas, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; Labfit-Health Products Research and Development Lda, UBImedical, Estrada Nacional 506, 6200-284 Covilhã, Portugal; Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
| | - Carla Cruz
- Departamento de Química, Universidade da Beira Interior, Rua Marquês de Ávila e Bolama, 6201-001 Covilhã, Portugal; RISE-Health, Departamento de Química, Faculdade de Ciências, Universidade da Beira Interior, Rua Marquês d'Ávila e Bolama 6201-001 Covilhã, Portugal.
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4
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Bogolyubov DS, Chistyakova LV, Travina AO, Sulatsky MI, Goodkov AV. New nucleolin-containing cytoplasmic bodies in an archamoebian protist Pelomyxa belevskii (Amoebozoa, Archamoebae, Pelobiontida). PROTOPLASMA 2025; 262:695-706. [PMID: 39805991 DOI: 10.1007/s00709-024-02017-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 12/05/2024] [Indexed: 01/16/2025]
Abstract
The representatives of the archamoebian genus Pelomyxa are amoeboid anaerobic protists that inhabit fresh-water anoxic sediments, and most of them are usually multinucleate. The cytoplasm of these unicellular organisms is highly complicated and contains numerous vacuoles of different types, as well as a wide range of prokaryotic endocytobionts, agglomerations of glycogen, lipids, etc. Among the great variety of cytoplasmic structures in P. belevskii, we identified novel organelles termed Cytoplasmic Nucleolin-Rich Bodies (CNRBs) due to their enrichment in nucleolin, a nuclear/nucleolar protein. The P. belevskii CNRBs differ significantly from known cytoplasmic nucleolin-related organelles encountered in some other eukaryotic cells, but their biological significance remains elusive. The work also provides the first description of the nuclear organization of P. belevskii. The nucleolar apparatus of P. belevskii contains little nucleolin, as determined by quantitative electron microscopic data, suggesting that it is inactive despite its morphological complexity. The presence of CNRBs in Pelomyxa is discussed in the context of the specific habitat conditions and biology of these unicellular eukaryotes.
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Affiliation(s)
- Dmitry S Bogolyubov
- Laboratory of Cell Morphology, Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, 194064, Russia.
| | - Ludmila V Chistyakova
- Zoological Institute of the Russian Academy of Sciences, St. Petersburg, 199034, Russia
| | - Alexandra O Travina
- Laboratory of Non-Coding DNA, Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, 194064, Russia
| | - Maksim I Sulatsky
- Laboratory of Cell Morphology, Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, 194064, Russia
| | - Andrew V Goodkov
- Laboratory of Cytology of Unicellular Organisms, Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, 194064, Russia
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5
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Chen L, Dickerhoff J, Zheng KW, Erramilli S, Feng H, Wu G, Onel B, Chen Y, Wang KB, Carver M, Lin C, Sakai S, Wan J, Vinson C, Hurley L, Kossiakoff AA, Deng N, Bai Y, Noinaj N, Yang D. Structural basis for nucleolin recognition of MYC promoter G-quadruplex. Science 2025; 388:eadr1752. [PMID: 40245140 PMCID: PMC12083725 DOI: 10.1126/science.adr1752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 01/28/2025] [Indexed: 04/19/2025]
Abstract
The MYC oncogene promoter G-quadruplex (MycG4) regulates transcription and is a prevalent G4 locus in immortal cells. Nucleolin, a major MycG4-binding protein, exhibits greater affinity for MycG4 than for nucleolin recognition element (NRE) RNA. Nucleolin's four RNA binding domains (RBDs) are essential for high-affinity MycG4 binding. We present the 2.6-angstrom crystal structure of the nucleolin-MycG4 complex, revealing a folded parallel three-tetrad G-quadruplex with two coordinating potassium ions (K+), interacting with RBD1, RBD2, and Linker12 through its 6-nucleotide (nt) central loop and 5' flanking region. RBD3 and RBD4 bind MycG4's 1-nt loops as demonstrated by nuclear magnetic resonance (NMR). Cleavage under targets and tagmentation sequencing confirmed nucleolin's binding to MycG4 in cells. Our results revealed a G4 conformation-based recognition by a regulating protein through multivalent interactions, suggesting that G4s are nucleolin's primary cellular substrates, indicating G4 epigenetic transcriptional regulation and helping G4-targeted drug discovery.
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Affiliation(s)
- Luying Chen
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Jonathan Dickerhoff
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Ke-wei Zheng
- School of Biomedical Sciences, Hunan University, Changsha 410082, China
| | - Satchal Erramilli
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA
| | - Hanqiao Feng
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Guanhui Wu
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Buket Onel
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Yuwei Chen
- R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Kai-Bo Wang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Megan Carver
- R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Clement Lin
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Saburo Sakai
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
- Biogeochemistry Research Center, Japan Agency for Marine-Earth Science and Technology, Kanagawa 237-0061, Japan
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Charles Vinson
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Laurence Hurley
- R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Anthony A Kossiakoff
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA
| | - Nanjie Deng
- Department of Chemistry and Physical Sciences, Pace University, New York, NY 10038, USA
| | - Yawen Bai
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicholas Noinaj
- Markey Center for Structural Biology, Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA
| | - Danzhou Yang
- Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA
- Purdue Institute for Drug Discovery Purdue University, West Lafayette, IN 47907, USA
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
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6
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Tian RQ, Gao Y, Hu XH, Jia MH, Fu LY, Pan D, Su SF, Shen XC, Xiao CD. Unmodified RNA sequences form unusual stable G-quadruplexes with potential anti-RSV and anti-angiogenesis applications. Commun Biol 2025; 8:474. [PMID: 40119117 PMCID: PMC11928468 DOI: 10.1038/s42003-025-07915-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 03/11/2025] [Indexed: 03/24/2025] Open
Abstract
DNA or RNA sequences with customizable designs form unique three-dimensional structures that bind to targets with high precision and strength, making them promising tools for medical diagnosis and therapy. However, their clinical use is limited by rapid clearance from blood and safety concerns. This study introduces a novel RNA-based structure called G-quadruplex, which requires no chemical modifications. These G-quadruplexes remain highly stable in biological fluids, retaining over 90% of their concentration after 96 h. Experiments confirm their strong binding to a cell surface protein (nucleolin) without significant cellular uptake, resulting in nearly zero harm to cells. They effectively block respiratory syncytial virus infection, suppress the growth and movement of human blood vessel cells, and prevent new blood vessel formation in chicken embryos, even without specialized delivery systems. These stable G-quadruplex structures demonstrate dual potential for treating cancers and viral infections, offering a versatile and safe strategy for future therapies.
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Affiliation(s)
- Rui-Qing Tian
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China
- Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, PR China
- Department of Hematology-oncology, The First People's Hospital of Guiyang, Guiyang, PR China
| | - Yue Gao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China
| | - Xiao-Hui Hu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China
| | - Meng-Hao Jia
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China
| | - Ling-Yun Fu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China
| | - Di Pan
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China
| | - Sheng-Fa Su
- Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, PR China.
| | - Xiang-Chun Shen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China.
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China.
| | - Chao-Da Xiao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China.
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, PR China.
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7
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Li S, Wang Z, Huang HD. Deciphering ovarian cancer heterogeneity through spatial transcriptomics, single-cell profiling, and copy number variations. PLoS One 2025; 20:e0317115. [PMID: 40036264 PMCID: PMC11878925 DOI: 10.1371/journal.pone.0317115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 12/21/2024] [Indexed: 03/06/2025] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) poses a formidable clinical challenge due to multidrug resistance (MDR) caused by tumor heterogeneity. To elucidate the intricate mechanisms underlying HGSOC heterogeneity, we conducted a comprehensive analysis of five single-cell transcriptomes and eight spatial transcriptomes derived from eight HGSOC patients. This study provides a comprehensive view of tumor heterogeneity across the spectrum of gene expression, copy number variation (CNV), and single-cell profiles. Our CNV analysis revealed intratumor heterogeneity by identifying distinct tumor clones, illuminating their evolutionary trajectories and spatial relationships. We further explored the homogeneity and heterogeneity of CNV across tumors to pinpoint the origin of heterogeneity. At the cellular level, single-cell RNA sequencing (scRNA seq) analysis identified three meta-programs that delineate the functional profile of tumor cells. The communication networks between tumor cell clusters exhibited unique patterns associated with the meta-programs governing these clusters. Notably, the ligand-receptor pair MDK - NCL emerged as a highly enriched interaction in tumor cell communication. To probe the functional significance of this interaction, we induced NCL overexpression in the SOVK3 cell line and observed enhanced tumor cell proliferation. These findings indicate that the MDK - NCL interaction plays a crucial role in promoting HGSOC tumor growth and may represent a promising therapeutic target. In conclusion, this study comprehensively unravels the multifaceted nature of HGSOC heterogeneity, providing potential therapeutic strategies for this challenging malignancy.
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Affiliation(s)
- Songyun Li
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, P.R. China
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, P. R. China
| | - Zhuo Wang
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, P.R. China
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, P. R. China
| | - Hsien-Da Huang
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, P.R. China
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, P. R. China
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8
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Helal MW, Faried MM, Salah SM, Ashraf M, Nasser N, Shawky Y, Hamdy S, Amir AE, Nabil W, El-Husseini DM. Comparative Analysis of Aptamer-Conjugated Chemical and Green Synthesized Gold Nanoparticles for Targeted Therapy in MCF-7 Cancer Cells. Appl Biochem Biotechnol 2025; 197:1678-1695. [PMID: 39601974 PMCID: PMC11953193 DOI: 10.1007/s12010-024-05091-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2024] [Indexed: 11/29/2024]
Abstract
Breast cancer remains a challenging health issue, demanding innovative treatment approaches that maximize efficacy while minimizing damage to healthy cells. Targeted therapy offers a promising strategy tailored to the unique characteristics of breast cancer tumors. Gold nanoparticles have been studied in the context of their therapeutic potential towards cancer treatment showing great success. Recently, aptamers were also investigated for their targeting efficiency towards specific receptors allowing their use in targeting delivery systems. In this study, computational analysis was used to confirm the strong binding between AS1411 aptamer and the nucleolin receptor extensively present on the surface of breast cancer cells, highlighting the aptamer's potential for specific targeting. Furthermore, we investigated and compared the use of AS1411 aptamer-conjugated chemically synthesized (GNPs) and flaxseed-green-synthesized (Fs-GNPs) gold nanoparticles as targeting therapeutic systems for breast cancer cells. Our results showed successful conjugation of the AS1411 aptamer with both, the GNPs and Fs-GNPs. Characterization of the nanoparticles and their conjugates validates their size, charge, and morphology, affirming the success of the conjugation process. Cytotoxicity assessments using the MTT assay demonstrated the effectiveness of the conjugates against breast cancer cells, with the AS1411-Fs-GNPs conjugate exhibiting higher inhibitory efficacy, featuring an IC50 value of 11.13 µg/ml. In contrast, they showed minimal effect on normal cells, emphasizing the selectivity and potential safety of these therapies. To our knowledge, this is the first report of conjugating AS1411 aptamer to green-synthesized gold nanoparticles and its use as a targeting therapeutic system.
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Affiliation(s)
- Mariam W Helal
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohanad M Faried
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | | | - Mazen Ashraf
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Nada Nasser
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Yasser Shawky
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Sara Hamdy
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Azza El Amir
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Wajeet Nabil
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Dalia M El-Husseini
- Nanomaterials Research and Synthesis Unit, Animal Health Research Institute (AHRI), Agricultural Research Center (ARC), Giza, Egypt.
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9
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Tao L, Xia J, Hu D, Zhang G, Gong Y, Yan J. Single-Cell Sequencing Reveals Heterogeneity and Interactions Between Epithelial Cells and Fibroblasts in Post-ESD Oesophageal Stricture. J Cell Mol Med 2025; 29:e70411. [PMID: 39910700 PMCID: PMC11798872 DOI: 10.1111/jcmm.70411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/13/2025] [Accepted: 01/24/2025] [Indexed: 02/07/2025] Open
Abstract
Oesophageal stricture, especially circumferential lesions, is a common complication of endoscopic submucosal dissection (ESD). However, the exact mechanisms underlying its development remain unclear. Consequently, understanding tissue microenvironment changes is crucial for identifying therapeutic targets. To address this, single-cell RNA sequencing (scRNA-seq) was performed on oesophageal stricture samples and normal controls. Alterations in cellular composition were observed, particularly in epithelial, endothelial, fibroblast and immune cells. A notable increase was observed in the number of differentiating suprabasal cell_2 (DFSC_2), which displayed pro-keratinizing traits. Detailed investigations revealed augmentation in a subset of these cells, characterised by elevated FTH1 and ECM1 expression, indicating their role in epithelial remodelling. Furthermore, fibroblast heterogeneity was demonstrated, with significant activation of myofibroblasts within stricture tissues. MDK-NCL, CXCL5/6-CXCR2, and TGFA-EGFR ligand-receptor pairs were enhanced in stricture tissues, mediating epithelial-stromal interactions. This study dissected the transcriptional landscape of postoperative oesophageal stricture tissues, providing valuable insights into stricture mechanisms and potential preventive strategies.
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Affiliation(s)
- Lulong Tao
- Department of GastroenterologyThe First Affiliated Hospital With Nanjing Medical UniversityNanjingChina
- The First Clinical Medical CollegeNanjing Medical UniversityNanjingChina
| | - Junjun Xia
- Department of GastroenterologyThe First Affiliated Hospital With Nanjing Medical UniversityNanjingChina
- The First Clinical Medical CollegeNanjing Medical UniversityNanjingChina
| | - Die Hu
- Department of GastroenterologyThe First Affiliated Hospital With Nanjing Medical UniversityNanjingChina
- The First Clinical Medical CollegeNanjing Medical UniversityNanjingChina
| | - Guoxin Zhang
- Department of GastroenterologyThe First Affiliated Hospital With Nanjing Medical UniversityNanjingChina
- The First Clinical Medical CollegeNanjing Medical UniversityNanjingChina
| | - Yaoyao Gong
- Department of GastroenterologyThe First Affiliated Hospital With Nanjing Medical UniversityNanjingChina
- The First Clinical Medical CollegeNanjing Medical UniversityNanjingChina
| | - Jin Yan
- Department of GastroenterologyThe First Affiliated Hospital With Nanjing Medical UniversityNanjingChina
- The First Clinical Medical CollegeNanjing Medical UniversityNanjingChina
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10
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Li G, Pu S, You L, Gao Y, Zhong Y, Zhao H, Fan D, Lu X. Innovative Strategies in Oncology: Bacterial Membrane Vesicle-Based Drug Delivery Systems for Cancer Diagnosis and Therapy. Pharmaceutics 2025; 17:58. [PMID: 39861706 PMCID: PMC11768367 DOI: 10.3390/pharmaceutics17010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/18/2024] [Accepted: 12/25/2024] [Indexed: 01/27/2025] Open
Abstract
Outer membrane vesicles (OMVs) are double-layered structures of nanoscale lipids released by gram-negative bacteria. They have the same membrane composition and characteristics as primitive cells, which enables them to penetrate cells and tissues efficiently. These OMVs exhibit excellent membrane stability, immunogenicity, safety, and permeability (which makes it easier for them to penetrate into tumour tissue), making them suitable for developing cancer vaccines and drug delivery systems. Recent studies have focused on engineering OMVs to enhance tumour-targeting capabilities, reduce toxicity, and extend circulation time in vivo. This article reviews the latest progress in OMV engineering for tumour treatment and discusses the challenges associated with the use of OMV-based antitumour therapy in clinical practice.
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Affiliation(s)
- Guodong Li
- College of Life Sciences, Northwest University, Xi’an 710069, China; (G.L.)
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi’an 710032, China
| | - Shuangpeng Pu
- College of Life Sciences, Northwest University, Xi’an 710069, China; (G.L.)
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi’an 710032, China
| | - Lisiyao You
- College of Life Sciences, Northwest University, Xi’an 710069, China; (G.L.)
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi’an 710032, China
| | - Yuan Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi’an 710032, China
| | - Yuexia Zhong
- Outpatient Department of the Second Affiliated Hospital of the Fourth Military Medical University, Xi’an 710032, China
| | - Huadong Zhao
- Department of General Surgery, Tangdu Hospital, Air Force Medical University, Xi’an 710038, China;
| | - Dong Fan
- Department of General Surgery, Tangdu Hospital, Air Force Medical University, Xi’an 710038, China;
| | - Xiyan Lu
- Outpatient Department of the Second Affiliated Hospital of the Fourth Military Medical University, Xi’an 710032, China
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11
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Kledus F, Dobrovolná M, Mergny JL, Brázda V. Asymmetric distribution of G-quadruplex forming sequences in genomes of retroviruses. Sci Rep 2025; 15:76. [PMID: 39747944 PMCID: PMC11696869 DOI: 10.1038/s41598-024-82613-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/06/2024] [Indexed: 01/04/2025] Open
Abstract
Retroviruses are among the most extensively studied viral families, both historically and in contemporary research. They are primarily investigated in the fields of viral oncogenesis, reverse transcription mechanisms, and other infection-specific aspects. These include the integration of endogenous retroviruses (ERVs) into host genomes, a process widely utilized in genetic engineering, and the ongoing search for HIV/AIDS treatment. G-quadruplexes (G4) have emerged as potential therapeutic targets in antiviral therapy and have been identified in important regulatory regions of viral genomes. In this study, we examine the presence of potential G-quadruplex-forming sequences (PQS) across all currently available unique retroviral genomes. Given that these retroviral genomes typically consist of single-stranded RNA (ssRNA) molecules, we also investigated whether the localization of PQSs is strand-dependent. This is particularly relevant since antisense transcripts have been detected in HIV, and ERV integration into the host genome involves reverse transcription from genomic positive strand ssRNA to double-stranded DNA (dsDNA), implicating both strands in this process. We show that in most mammalian retroviruses, including human retroviruses, PQSs are significantly more prevalent on the negative (antisense) strand, with some notable exceptions such as HIV-1. In sharp contrast, avian retroviruses exhibit a higher prevalence of PQSs on the positive (sense) strand.
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Affiliation(s)
- Filip Kledus
- Institute of Biophysics , Czech Academy of Sciences , Královopolská 135, Brno, 612 65, Czech Republic
- Faculty of Science , National Centre for Biomolecular Research Masaryk University , Kamenice 5, Brno, 625 00, Czech Republic
| | - Michaela Dobrovolná
- Institute of Biophysics , Czech Academy of Sciences , Královopolská 135, Brno, 612 65, Czech Republic
- Faculty of Chemistry , Brno University of Technology , Purkyňova 118, Brno, 61200, Czech Republic
| | - Jean-Louis Mergny
- Institute of Biophysics , Czech Academy of Sciences , Královopolská 135, Brno, 612 65, Czech Republic
- Laboratoire d'Optique et Biosciences (LOB) , Ecole Polytechnique CNRS INSERM Institut Polytechnique de Paris , Palaiseau, 91120, France
| | - Václav Brázda
- Institute of Biophysics , Czech Academy of Sciences , Královopolská 135, Brno, 612 65, Czech Republic.
- Faculty of Chemistry , Brno University of Technology , Purkyňova 118, Brno, 61200, Czech Republic.
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12
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Ji Q, Yang Q, Ou M, Hong M. Simultaneous Down-Regulation of Intracellular MicroRNA-21 and hTERT mRNA Using AS1411-Functionallized Gold Nanoprobes to Achieve Targeted Anti-Tumor Therapy. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:1956. [PMID: 39683343 DOI: 10.3390/nano14231956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024]
Abstract
Telomerase presents over-expression in most cancer cells and has been used as a near-universal marker of cancer. Studies have revealed that inhibiting telomerase activity by utilizing oligonucleotides to down-regulate the expression of intracellular human telomerase reverse-transcriptase (hTERT) mRNA is an effective method of achieving anti-tumor therapy. Considering that oncogenic microRNA-21 has been proven to indirectly up-regulate hTERT expression and drive cancer metastasis and aggression through increased telomerase activity, here, we constructed an AS1411-functionallized oligonucleotide-conjugated gold nanoprobe (Au nanoprobe) to simultaneously down-regulate intracellular microRNA-21 and hTERT mRNA by using anti-sense oligonucleotide technology to explore their targeted anti-tumor therapy effect. In vitro cell studies demonstrated that Au nanoprobes could effectively induce apoptosis and inhibit the proliferation of cancer cells by down-regulating intracellular hTERT activity. In vivo imaging and anti-tumor studies revealed that Au nanoprobes could accumulate at the tumor site and inhibit the growth of MCF-7 tumor xenografted on balb/c nude mice, thus having potential for anti-tumor therapy.
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Affiliation(s)
- Qinghong Ji
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252059, China
| | - Qiangqiang Yang
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252059, China
| | - Mengyao Ou
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252059, China
| | - Min Hong
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252059, China
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13
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Steinkellner H, Madritsch S, Kluge M, Seipel T, Sarne V, Huber A, Schosserer M, Oberle R, Neuhaus W, Beribisky AV, Laccone F. RNA Sequencing and Weighted Gene Co-Expression Network Analysis Highlight DNA Replication and Key Genes in Nucleolin-Depleted Hepatoblastoma Cells. Genes (Basel) 2024; 15:1514. [PMID: 39766782 PMCID: PMC11675179 DOI: 10.3390/genes15121514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Nucleolin is a major component of the nucleolus and is involved in various aspects of ribosome biogenesis. However, it is also implicated in non-nucleolar functions such as cell cycle regulation and proliferation, linking it to various pathologic processes. The aim of this study was to use differential gene expression analysis and Weighted Gene Co-expression Network analysis (WGCNA) to identify nucleolin-related regulatory pathways and possible key genes as novel therapeutic targets for cancer, viral infections and other diseases. METHODS We used two different siRNAs to downregulate the expression of nucleolin in a human hepatoblastoma (HepG2) cell line. We carried out RNA-sequencing (RNA-Seq), performed enrichment analysis of the pathways of the differentially expressed genes (DEGs) and identified protein-protein interaction (PPI) networks. RESULTS Both siRNAs showed high knockdown efficiency in HepG2 cells, resulting in the disruption of the nucleolar architecture and the downregulation of rRNA gene expression, both downstream hallmarks of a loss of nucleolin function. RNA-Seq identified 44 robust DEGs in both siRNA cell models. The enrichment analysis of the pathways of the downregulated genes confirmed the essential role of nucleolin in DNA replication and cell cycle processes. In addition, we identified seven hub genes linked to NCL: MCM6, MCM3, FEN1, MYBL2, MSH6, CDC6 and RBM14; all are known to be implicated in DNA replication, cell cycle progression and oncogenesis. CONCLUSIONS Our findings demonstrate the functional consequences of nucleolin depletion in HepG2 and confirm the importance of nucleolin in DNA replication and cell cycle processes. These data will further enhance our understanding of the molecular and pathologic mechanisms of nucleolin and provide new therapeutic perspectives in disease.
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Affiliation(s)
- Hannes Steinkellner
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
| | - Silvia Madritsch
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
| | - Mara Kluge
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
| | - Teresa Seipel
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
| | - Victoria Sarne
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
- Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, 1090 Vienna, Austria
| | - Anna Huber
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
- Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, 1090 Vienna, Austria
| | - Markus Schosserer
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
| | - Raimund Oberle
- Center for Pathobiochemistry and Genetics, Institute of Medical Chemistry and Pathobiochemistry, Medical University of Vienna, 1090 Vienna, Austria
| | - Winfried Neuhaus
- Competence Unit Molecular Diagnostics, Center Health and Bioresources, AIT-Austrian Institute of Technology GmbH, 1210 Vienna, Austria;
- Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, 3500 Krems an der Donau, Austria
| | - Alexander V. Beribisky
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
| | - Franco Laccone
- Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria (A.H.); (A.V.B.); (F.L.)
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14
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Lopes-Nunes J, Oliveira PA, Cruz C. Enhanced targeted liposomal delivery of imiquimod via aptamer functionalization for head and neck cancer therapy. Colloids Surf B Biointerfaces 2024; 243:114121. [PMID: 39094208 DOI: 10.1016/j.colsurfb.2024.114121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/21/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024]
Abstract
The incidence of head and neck cancers, particularly those associated with Human Papillomavirus (HPV) infections, has been steadily increasing. Conventional therapies exhibit limitations and drawbacks, prompting the exploration of new strategies over the years, with nanomedicine approaches, especially liposomes gaining relevance. Additionally, the functionalization of liposomes with aptamers enables selective delivery to target cells. For instance, AT11 can serve as a targeting moiety for cancer cells due to its high affinity for nucleolin, a protein overexpressed on the cancer cell's surface. In this study, liposomes functionalized with AT11 are proposed as drug delivery systems for imiquimod (IQ), aiming to maximize its potential as an anticancer agent for HPV-related cancers. To this end, firstly liposomes were produced through the ethanol injection method, functionalized with AT11-TEG-Cholesteryl, and characterized using dynamic light scattering. The obtained liposomes presented suitable properties for cancer therapy (with sizes from 120 to 140 nm and low polydispersity PDI < 0.16) and were further evaluated in terms of potential anticancer effects. AT11 IQ-associated liposomes allowed a selective delivery of IQ towards a tongue cancer cell line (UPCI-SCC-154) relative to the non-malignant cell line (Het1A). Specifically, they induced a selective reduction of the cell viability (∼52 % versus ∼113 %; p < 0.0001), proliferation (∼68 % versus ∼102 %; p<0.0001) and increased cell death (∼7-fold increase; p < 0.0001)). Additionally, they decreased the migration (from ∼24 % to ∼8 %; p < 0.0001) and invasion (to 11 %; p = 0.0047) capacities of the cancer cells. In summary, the produced liposomes represent a promising approach to enhance the anticancer potential of IQ in head and neck cancer, particularly in tongue cancer.
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Affiliation(s)
- Jéssica Lopes-Nunes
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Paula A Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Inov4Agro, Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal
| | - Carla Cruz
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; Departamento de Química, Universidade da Beira Interior, Rua Marquês de Ávila e Bolama, Covilhã 6201-001, Portugal.
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15
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Huang BT, Lai WY, Yeh CL, Tseng YT, Peck K, Yang PC, Lin EPY. AptBCis1, An Aptamer-Cisplatin Conjugate, Is Effective in Lung Cancer Leptomeningeal Carcinomatosis. ACS NANO 2024; 18:27905-27916. [PMID: 39360769 PMCID: PMC11483943 DOI: 10.1021/acsnano.4c04680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 10/16/2024]
Abstract
Treatment of lung cancer leptomeningeal carcinomatosis (LM) remains challenging partly due to the biological nature of the blood-brain barrier (BBB). Cisplatin has limited effects on LM, and it is notorious for neurotoxicity. Aptamers are small oligonucleotides considered as antibody surrogates. Here we report a DNA therapeutics, AptBCis1. AptBCis1 is a cisplatin-conjugated, BBB-penetrating, and cancer-targeting DNA aptamer. Its backbone, AptB1, was identified via in vivo SELEX using lung cancer LM orthotopic mouse models. The AptB1 binds to EAAT2, Nucleolin, and YB-1 proteins. Treatment with AptBCis1 1 mg/kg (equivalent to cisplatin 0.35 mg/kg) showed superior tumor suppressive effects compared to cisplatin 2 mg/kg in mice with lung cancer LM diseases. The cerebrospinal fluid platinum concentration in the AptBCis1 group was 10% of that in the cisplatin group. The data suggested the translational potential of AptBCis1 in lung cancer with LM and in cancers in which platinum-based chemotherapy remains as the standard of care.
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Affiliation(s)
- Bo-Tsang Huang
- Division
of Thoracic Medicine, Department of Internal Medicine, School of Medicine,
College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Wei-Yun Lai
- Division
of Thoracic Medicine, Department of Internal Medicine, School of Medicine,
College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department
of Medical Research, Taipei Medical University
Hospital, Taipei 110, Taiwan
| | - Chen-Lin Yeh
- Division
of Thoracic Medicine, Department of Internal Medicine, School of Medicine,
College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yi-Ting Tseng
- Division
of Thoracic Medicine, Department of Internal Medicine, School of Medicine,
College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Konan Peck
- Institute
of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Pan-Chyr Yang
- Institute
of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Division
of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan
| | - Emily Pei-Ying Lin
- Division
of Thoracic Medicine, Department of Internal Medicine, School of Medicine,
College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division
of Thoracic Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
- Department
of Medical Research, Taipei Medical University
Hospital, Taipei 110, Taiwan
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16
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Sun L, Meng H, Liu T, Zhao Q, Xia M, Zhao Z, Qian Y, Cui H, Zhong X, Chai K, Tian Y, Sun Y, Zhu B, Di J, Shui G, Zhang L, Zheng J, Guo S, Liu Y. Nucleolin malonylation as a nuclear-cytosol signal exchange mechanism to drive cell proliferation in Hepatocarcinoma by enhancing AKT translation. J Biol Chem 2024; 300:107785. [PMID: 39305961 PMCID: PMC11525140 DOI: 10.1016/j.jbc.2024.107785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 10/18/2024] Open
Abstract
Cancer cells undergo metabolic reprogramming that is intricately linked to malignancy. Protein acylations are especially responsive to metabolic changes, influencing signal transduction pathways and fostering cell proliferation. However, as a novel type of acylations, the involvement of malonylation in cancer remains poorly understood. In this study, we observed a significant reduction in malonyl-CoA levels in hepatocellular carcinoma (HCC), which correlated with a global decrease in malonylation. Subsequent nuclear malonylome analysis unveiled nucleolin (NCL) malonylation, which was notably enhanced in HCC biopsies. we demonstrated that NCL undergoes malonylation at lysine residues 124 and 398. This modification triggers the translocation of NCL from the nucleolus to nucleoplasm and cytoplasm, binding to AKT mRNA, and promoting AKT translation in HCC. Silencing AKT expression markedly attenuated HCC cell proliferation driven by NCL malonylation. These findings collectively highlight nuclear signaling in modulating AKT expression, suggesting NCL malonylation as a novel mechanism through which cancer cells drive cell proliferation.
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Affiliation(s)
- Liang Sun
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hanjing Meng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Tao Liu
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China
| | - Qiong Zhao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Mingyi Xia
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhongjun Zhao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yuting Qian
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hao Cui
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xuefei Zhong
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Keli Chai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yang Tian
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yang Sun
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bao Zhu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiehui Di
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Lianjun Zhang
- National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China
| | - Junnian Zheng
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Shutao Guo
- Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China.
| | - Yong Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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17
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Yang L, Niu K, Wang J, Shen W, Jiang R, Liu L, Song W, Wang X, Zhang X, Zhang R, Wei D, Fan M, Jia L, Tao K. Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD. J Hepatol 2024; 81:651-666. [PMID: 38679071 DOI: 10.1016/j.jhep.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 04/03/2024] [Accepted: 04/15/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND & AIMS Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA. METHODS Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples. RESULTS Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA. CONCLUSION NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA. IMPACT AND IMPLICATIONS Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA.
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Affiliation(s)
- Long Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Kunwei Niu
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jianlin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Weiwei Shen
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Rui Jiang
- Department of Anesthesiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lu Liu
- College of Life Sciences, Northwest University, Xi'an, China
| | - Wenjie Song
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xudan Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Ruohan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Dan Wei
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Ming Fan
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lintao Jia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
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18
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Huang WC, Hsu KW, Peng PH, Zeng WT, Gu TJ, Lin LJ, Hsieh MT, Lee DY, Chang GD. Application of Reducible Covalent Capture Purification for Resolving Persulfidome and Nucleolin S-Sulfhydration. Anal Chem 2024; 96:14186-14196. [PMID: 39171919 DOI: 10.1021/acs.analchem.4c02717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Protein S-sulfhydration involves the regulation of various protein functions, and resolving the S-sulfhydrated proteome (persulfidome) allows for a deeper exploration of various redox regulations. Therefore, we designed a reducible covalent capture method for isolating S-sulfhydrated proteins, which can analyze the persulfidome in biological samples and monitor specific S-sulfhydrated proteins. In this study, we applied this method to reveal the S-sulfhydration levels of proteins, including 3-phosphoglyceraldehyde dehydrogenase, NFκB/p65, and nucleolin. Furthermore, this technique can be used to enrich S-sulfhydrated peptides, aiding in the determination of protein S-sulfhydration modification sites. Finally, we observed that the S-sulfhydration and oxidation of nucleolin on the C543 residue correlate with its nuclear translocation, downstream regulation of p53, Bcl-xL, and Bcl-2 RNA levels and protein expression, as well as the protective function against oxidative stress. Therefore, this method may facilitate the understanding of the regulation of protein function by redox perturbation.
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Affiliation(s)
- Wei-Chieh Huang
- Graduate Institute of Biochemical Sciences, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 106, Taiwan
| | - Kai-Wen Hsu
- Drug Development Center, Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- Research Center for Cancer Biology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- Institute of Translational Medicine and New Drug Development, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Pei-Hua Peng
- Drug Development Center, Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Wan-Ting Zeng
- Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Ting-Jia Gu
- Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Li-Jie Lin
- Drug Development Center, Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- Research Center for Cancer Biology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Min-Tsang Hsieh
- School of Pharmacy, China Medical University, Taichung 406040, Taiwan
- Drug Development Center, China Medical University, Taichung 406040, Taiwan
- Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan
| | - Der-Yen Lee
- Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Geen-Dong Chang
- Graduate Institute of Biochemical Sciences, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 106, Taiwan
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19
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Lee LCC, Lo KKW. Shining New Light on Biological Systems: Luminescent Transition Metal Complexes for Bioimaging and Biosensing Applications. Chem Rev 2024; 124:8825-9014. [PMID: 39052606 PMCID: PMC11328004 DOI: 10.1021/acs.chemrev.3c00629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Luminescence imaging is a powerful and versatile technique for investigating cell physiology and pathology in living systems, making significant contributions to life science research and clinical diagnosis. In recent years, luminescent transition metal complexes have gained significant attention for diagnostic and therapeutic applications due to their unique photophysical and photochemical properties. In this Review, we provide a comprehensive overview of the recent development of luminescent transition metal complexes for bioimaging and biosensing applications, with a focus on transition metal centers with a d6, d8, and d10 electronic configuration. We elucidate the structure-property relationships of luminescent transition metal complexes, exploring how their structural characteristics can be manipulated to control their biological behavior such as cellular uptake, localization, biocompatibility, pharmacokinetics, and biodistribution. Furthermore, we introduce the various design strategies that leverage the interesting photophysical properties of luminescent transition metal complexes for a wide variety of biological applications, including autofluorescence-free imaging, multimodal imaging, organelle imaging, biological sensing, microenvironment monitoring, bioorthogonal labeling, bacterial imaging, and cell viability assessment. Finally, we provide insights into the challenges and perspectives of luminescent transition metal complexes for bioimaging and biosensing applications, as well as their use in disease diagnosis and treatment evaluation.
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Affiliation(s)
- Lawrence Cho-Cheung Lee
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Units 1503-1511, 15/F, Building 17W, Hong Kong Science Park, New Territories, Hong Kong, P. R. China
| | - Kenneth Kam-Wing Lo
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China
- State Key Laboratory of Terahertz and Millimeter Waves, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China
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20
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Maravelez Acosta VA, Crisóstomo Vázquez MDP, Eligio García L, Franco Sandoval LO, Castro Pérez D, Patiño López G, Medina Contreras O, Jiménez Cardoso E. Tumor-Suppressive Cross-Linking of Anti- T. cruzi Antibodies in Acute Lymphoblastic Leukemia. Int J Mol Sci 2024; 25:8307. [PMID: 39125875 PMCID: PMC11313589 DOI: 10.3390/ijms25158307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
Parasites have been associated with possible anticancer activity, including Trypanosoma cruzi, which has been linked to inhibiting the growth of solid tumors. To better understand this antitumor effect, we investigated the association of anti-T. cruzi antibodies with B cells of the acute lymphoblastic leukemia (ALL) SUPB15 cell line. The antibodies were generated in rabbits. IgGs were purified by affinity chromatography. Two procedures (flow cytometry (CF) and Western blot(WB)) were employed to recognize anti-T. cruzi antibodies on SUPB15 cells. We also used CF to determine whether the anti-T. cruzi antibodies could suppress SUPB15 cells. The anti-T. cruzi antibodies recognized 35.5% of the surface antigens of SUPB15. The complement-dependent cytotoxicity (CDC) results demonstrate the cross-suppression of anti-T. cruzi antibodies on up to 8.4% of SUPB15 cells. For the WB analysis, a band at 100 kDa with high intensity was sequenced using mass spectrometry, identifying the protein as nucleolin. This protein may play a role in the antitumor effect on T. cruzi. The anti-T. cruzi antibodies represent promising polyclonal antibodies that have the effect of tumor-suppressive cross-linking on cancer cells, which should be further investigated.
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Affiliation(s)
- Víctor Alberto Maravelez Acosta
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.); (M.d.P.C.V.); (L.E.G.); (L.O.F.S.); (D.C.P.)
| | - María del Pilar Crisóstomo Vázquez
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.); (M.d.P.C.V.); (L.E.G.); (L.O.F.S.); (D.C.P.)
| | - Leticia Eligio García
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.); (M.d.P.C.V.); (L.E.G.); (L.O.F.S.); (D.C.P.)
| | - Luz Ofelia Franco Sandoval
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.); (M.d.P.C.V.); (L.E.G.); (L.O.F.S.); (D.C.P.)
| | - Denia Castro Pérez
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.); (M.d.P.C.V.); (L.E.G.); (L.O.F.S.); (D.C.P.)
| | - Genaro Patiño López
- Unidad de Investigación en Inmunología y Proteomica, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico;
| | - Oscar Medina Contreras
- Unidad de Investigación Epidemiologica en Endocrinologia y Nutricion, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico;
| | - Enedina Jiménez Cardoso
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.); (M.d.P.C.V.); (L.E.G.); (L.O.F.S.); (D.C.P.)
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21
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Chen Y, Yang J, Wang C, Wang T, Zeng Y, Li X, Zuo Y, Chen H, Zhang C, Cao Y, Sun C, Wang M, Cao X, Ge X, Liu Y, Zhang G, Deng Y, Peng C, Lu A, Lu J. Aptamer-functionalized triptolide with release controllability as a promising targeted therapy against triple-negative breast cancer. J Exp Clin Cancer Res 2024; 43:207. [PMID: 39054545 PMCID: PMC11270970 DOI: 10.1186/s13046-024-03133-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
Targeted delivery and precise release of toxins is a prospective strategy for the treatment of triple-negative breast cancer (TNBC), yet the flexibility to incorporate both properties simultaneously remains tremendously challenging in the X-drug conjugate fields. As critical components in conjugates, linkers could flourish in achieving optimal functionalities. Here, we pioneered a pH-hypersensitive tumor-targeting aptamer AS1411-triptolide conjugate (AS-TP) to achieve smart release of the toxin and targeted therapy against TNBC. The multifunctional acetal ester linker in the AS-TP site-specifically blocked triptolide toxicity, quantitatively sustained aptamer targeting, and ensured the circulating stability. Furthermore, the aptamer modification endowed triptolide with favorable water solubility and bioavailability and facilitated endocytosis of conjugated triptolide by TNBC cells in a nucleolin-dependent manner. The integrated superiorities of AS-TP promoted the preferential intra-tumor triptolide accumulation in xenografted TNBC mice and triggered the in-situ triptolide release in the weakly acidic tumor microenvironment, manifesting striking anti-TNBC efficacy and virtually eliminated toxic effects beyond clinical drugs. This study illustrated the therapeutic potential of AS-TP against TNBC and proposed a promising concept for the development of nucleic acid-based targeted anticancer drugs.
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Affiliation(s)
- Yao Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jirui Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Chuanqi Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Tianbao Wang
- Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Yingjie Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xiao Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yi Zuo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Hongyu Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Chaozheng Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yuening Cao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Chen Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Maolin Wang
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong Province, China
| | - Xiujun Cao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xian Ge
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yilan Liu
- Hematology Department, The General Hospital of the Western Theater Command PLA, Chengdu, 611137, China
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Yun Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Aiping Lu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
| | - Jun Lu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
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22
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McCool MA, Bryant CJ, Abriola L, Surovtseva YV, Baserga SJ. The cytidine deaminase APOBEC3A regulates nucleolar function to promote cell growth and ribosome biogenesis. PLoS Biol 2024; 22:e3002718. [PMID: 38976757 PMCID: PMC11257408 DOI: 10.1371/journal.pbio.3002718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 07/18/2024] [Accepted: 06/20/2024] [Indexed: 07/10/2024] Open
Abstract
Cancer initiates as a consequence of genomic mutations and its subsequent progression relies in part on increased production of ribosomes to maintain high levels of protein synthesis for unchecked cell growth. Recently, cytidine deaminases have been uncovered as sources of mutagenesis in cancer. In an attempt to form a connection between these 2 cancer driving processes, we interrogated the cytidine deaminase family of proteins for potential roles in human ribosome biogenesis. We identified and validated APOBEC3A and APOBEC4 as novel ribosome biogenesis factors through our laboratory's established screening platform for the discovery of regulators of nucleolar function in MCF10A cells. Through siRNA depletion experiments, we highlight APOBEC3A's requirement in making ribosomes and specific role within the processing and maturation steps that form the large subunit 5.8S and 28S ribosomal (r)RNAs. We demonstrate that a subset of APOBEC3A resides within the nucleolus and associates with critical ribosome biogenesis factors. Mechanistic insight was revealed by transient overexpression of both wild-type and a catalytically dead mutated APOBEC3A, which both increase cell growth and protein synthesis. Through an innovative nuclear RNA sequencing methodology, we identify only modest predicted APOBEC3A C-to-U target sites on the pre-rRNA and pre-mRNAs. Our work reveals a potential direct role for APOBEC3A in ribosome biogenesis likely independent of its editing function. More broadly, we found an additional function of APOBEC3A in cancer pathology through its function in ribosome biogenesis, expanding its relevance as a target for cancer therapeutics.
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Affiliation(s)
- Mason A. McCool
- Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Carson J. Bryant
- Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Laura Abriola
- Yale Center for Molecular Discovery, Yale University, West Haven, Connecticut, United States of America
| | - Yulia V. Surovtseva
- Yale Center for Molecular Discovery, Yale University, West Haven, Connecticut, United States of America
| | - Susan J. Baserga
- Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
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23
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Mills J, Tessari A, Anastas V, Kumar DS, Rad NS, Lamba S, Cosentini I, Reers A, Zhu Z, Miles WO, Coppola V, Cocucci E, Magliery TJ, Shive H, Davies AE, Rizzotto L, Croce CM, Palmieri D. Nucleolin acute degradation reveals novel functions in cell cycle progression and division in TNBC. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.17.599429. [PMID: 38948867 PMCID: PMC11212942 DOI: 10.1101/2024.06.17.599429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Nucleoli are large nuclear sub-compartments where vital processes, such as ribosome assembly, take place. Technical obstacles still limit our understanding of the biological functions of nucleolar proteins in cell homeostasis and cancer pathogenesis. Since most nucleolar proteins are essential, their abrogation cannot be achieved through conventional approaches. Additionally, the biological activities of many nucleolar proteins are connected to their physiological concentration. Thus, artificial overexpression might not fully recapitulate their endogenous functions. Proteolysis-based approaches, such as the Auxin Inducible Degron (AID) system paired with CRISPR/Cas9 knock-in gene-editing, have the potential to overcome these limitations, providing unprecedented characterization of the biological activities of endogenous nucleolar proteins. We applied this system to endogenous nucleolin (NCL), one of the most abundant nucleolar proteins, and characterized the impact of its acute depletion on Triple-Negative Breast Cancer (TNBC) cell behavior. Abrogation of endogenous NCL reduced proliferation and caused defective cytokinesis, resulting in bi-nucleated tetraploid cells. Bioinformatic analysis of patient data, and quantitative proteomics using our experimental NCL-depleted model, indicated that NCL levels are correlated with the abundance of proteins involved in chromosomal segregation. In conjunction with its effects on sister chromatid dynamics, NCL abrogation enhanced the anti-proliferative effects of chemical inhibitors of mitotic modulators such as the Anaphase Promoting Complex. In summary, using the AID system in combination with CRISPR/Cas9 for endogenous gene editing, our findings indicate a novel role for NCL in supporting the completion of the cell division in TNBC models, and that its abrogation could enhance the therapeutic activity of mitotic-progression inhibitors.
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Affiliation(s)
- Joseph Mills
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, 43210, Columbus, OH, USA
| | - Anna Tessari
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
| | - Vollter Anastas
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Graduate School of Biomedical Sciences, Tufts University, 02155, Boston, MA, USA
| | - Damu Sunil Kumar
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
| | - Nastaran Samadi Rad
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Biomedical Sciences Graduate Program, The Ohio State University, 43210, Columbus, OH, USA
| | - Saranya Lamba
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
| | - Ilaria Cosentini
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Current address: Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), Palermo, Italy
| | - Ashley Reers
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Current address: Department of Ecology and Evolutionary Biology, Tulane University, 70118, New Orleans, LA, USA
| | - Zirui Zhu
- Department of Chemistry and Biochemistry, The Ohio State University, 43210, Columbus, OH, USA
- Chemistry Graduate Program, The Ohio State University, 43210, Columbus, OH, USA
| | - Wayne O Miles
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
| | - Vincenzo Coppola
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University-James Cancer Hospital and Solove Research Institute, 43210, Columbus, OH, USA
| | - Emanuele Cocucci
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 43210, Columbus, OH, USA
| | - Thomas J. Magliery
- Department of Chemistry and Biochemistry, The Ohio State University, 43210, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University-James Cancer Hospital and Solove Research Institute, 43210, Columbus, OH, USA
| | - Heather Shive
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 43210, Columbus, OH, USA
- Current address: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Alexander E. Davies
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 43210, Columbus, OH, USA
- Current address: Division of Oncological Sciences, Department of Pediatrics, Cancer Early Detection Advanced Research Center, School of Medicine, Oregon Health and Science University, 97239, Portland, OR, USA
| | - Lara Rizzotto
- Gene Editing Shared Resource, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
| | - Carlo M. Croce
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
| | - Dario Palmieri
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, 43210, Columbus, OH, USA
- The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
- Gene Editing Shared Resource, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, 43210, Columbus, OH, USA
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Shariat Razavi F, Kouchak M, Sistani Karampour N, Mahdavinia M, Nazari Khorasgani Z, Rezaie A, Rahbar N. AS1411aptamer conjugated liposomes for targeted delivery of arsenic trioxide in mouse xenograft model of melanoma cancer. J Liposome Res 2024; 34:288-302. [PMID: 37843918 DOI: 10.1080/08982104.2023.2271046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/10/2023] [Indexed: 10/18/2023]
Abstract
Development of AS1411aptamer-conjugated liposomes for targeted delivery of arsenic trioxide is the primary goal of this study. AS1411aptamer was used as ligand to target nucleolin, which is highly expressed on the surface of melanoma cancer cells. The targeted liposomes were constructed by the thin film method, and arsenic trioxide was loaded as cobalt (II) hydrogen arsenite (CHA) to increase the loading efficiency and stability of the liposomes. The liposomal structure was characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and field emission scanning electron microscopy (FESEM). In addition, particle sizes and zeta potential of the CHA-loaded liposomes (CHAL) and aptamer-functionalized CHA-loaded liposomes (AP-CHAL) were determined. In vitro cytotoxicity of CHAL and AP-CHAL were evaluated using MTT assay in murine melanoma (B16) and mouse embryonic fibroblast (MEF) cell lines. The encapsulation efficiency of CHAL and AP-CHAL was reported as 60.2 ± 6.5% and 58.7 ± 4.2%, respectively. In vivo antitumor activity of CHAL and AP-CHAL in the B16 tumor-xenograft mouse model was dramatically observed. All mice of both groups survived until the end of treatment and showed body weight gain. The tumor protrusion completely disappeared in 50% of the mice in these groups. Furthermore, histopathology studies demonstrated that CHAL and AP-CHAL did not induce significant toxicity in healthy mice tissues. However, unlike the CHAL group, which showed an initial increase in tumor volume, a specific antitumor effect was observed in the AP-CHAL group from the beginning of treatment. The results showed that AP-CHAL can be used as an effective drug delivery system with high potential in the treatment of solid tumors.
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Affiliation(s)
- Fatemeh Shariat Razavi
- Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Pharmaceutics, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Kouchak
- Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Pharmaceutics, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Neda Sistani Karampour
- Marine Pharmaceutical Science Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Pharmacology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masoud Mahdavinia
- Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Zahra Nazari Khorasgani
- Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Annahita Rezaie
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Nadereh Rahbar
- Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Zhu Y, Li X, Zhang Q, Yang X, Sun X, Pan Y, Yuan X, Ma Y, Xu B, Yang Z. Aptamer AS411 interacts with the KRAS promoter/hnRNP A1 complex and shows increased potency against drug-resistant lung cancer. RSC Med Chem 2024; 15:1515-1526. [PMID: 38784467 PMCID: PMC11110790 DOI: 10.1039/d3md00752a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/15/2024] [Accepted: 02/22/2024] [Indexed: 05/25/2024] Open
Abstract
G-quadruplex (G4) aptamers that can competitively binding protein with oncogene promoter G4 hold promise for cancer treatment. In this study, a neutral cytidinyl lipid, DNCA, was shown to transfect and deliver G4 aptamers (AS1411, TBA) into tumour cells, including multidrug-resistant tumour cells, and their nuclear localizations were clearly detected. Both AS1411/DNCA and TBA/DNCA showed excellent antitumour efficacies in the drug-resistant non-small cell lung cancer cell line A549/TXL at a low concentration (100 nM). Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was identified as a new target of AS1411 and TBA. The binding affinities were measured, and the Kd values of AS1411/hnRNP A1 and TBA/hnRNP A1 were 17.5 nM and 21.1 nM, respectively. Then the expression of KRAS mRNA in A549/TXL cells was found to be higher than that in A549 cells, and KRAS mRNA was reduced by approximately 40% after administration of AS1411 or TBA in A549/TXL cells. Further, it was confirmed for the first time that AS1411 targeted not only hnRNP A1 but also the KRAS promoter/hnRNP A1 complexes. And although TBA cannot target the KRAS promoter/hnRNP A1 complexes, the biolayer interferometry (BLI) experiment showed that TBA and AS1411 have similar effects on several key proteins in tumour cells, especially hnRNP A1. Molecular docking and molecular dynamics simulation showed that AS1411 and the KRAS promoter bound to the same domain of hnRNP A1 protein, while TBA bound to another domain.
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Affiliation(s)
- Yuejie Zhu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Xiang Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Qi Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Xiantao Yang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
- School of Pharmacy, Chengdu Medical College 783 Xindu Avenue, Xindu District Chengdu 610500 China
| | - Xudong Sun
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Yi Pan
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Xia Yuan
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Yuan Ma
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Bo Xu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
| | - Zhenjun Yang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Beijing 100191 China +86 10 82802503 +86 10 82802503
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26
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Huynh M, Vinck R, Gibert B, Gasser G. Strategies for the Nuclear Delivery of Metal Complexes to Cancer Cells. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2311437. [PMID: 38174785 DOI: 10.1002/adma.202311437] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/20/2023] [Indexed: 01/05/2024]
Abstract
The nucleus is an essential organelle for the function of cells. It holds most of the genetic material and plays a crucial role in the regulation of cell growth and proliferation. Since many antitumoral therapies target nucleic acids to induce cell death, tumor-specific nuclear drug delivery could potentiate therapeutic effects and prevent potential off-target side effects on healthy tissue. Due to their great structural variety, good biocompatibility, and unique physico-chemical properties, organometallic complexes and other metal-based compounds have sparked great interest as promising anticancer agents. In this review, strategies for specific nuclear delivery of metal complexes are summarized and discussed to highlight crucial parameters to consider for the design of new metal complexes as anticancer drug candidates. Moreover, the existing opportunities and challenges of tumor-specific, nucleus-targeting metal complexes are emphasized to outline some new perspectives and help in the design of new cancer treatments.
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Affiliation(s)
- Marie Huynh
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry of Life and Health Sciences, Laboratory for Inorganic Chemistry, Paris, F-75005, France
- Gastroenterology and technologies for Health, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS5286, Université Lyon 1, Lyon, 69008, France
| | - Robin Vinck
- Orano, 125 avenue de Paris, Châtillon, 92320, France
| | - Benjamin Gibert
- Gastroenterology and technologies for Health, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS5286, Université Lyon 1, Lyon, 69008, France
| | - Gilles Gasser
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry of Life and Health Sciences, Laboratory for Inorganic Chemistry, Paris, F-75005, France
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Hu X, Chen G, Huang Y, Cheng Q, Zhuo J, Su R, He C, Wu Y, Liu Z, Yang B, Wang S, Meng L, Zheng S, Lu D, Wei Q, Yang J, Wei X, Chen R, Xu X. Integrated Multiomics Reveals Silencing of has_circ_0006646 Promotes TRIM21-Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306915. [PMID: 38357830 PMCID: PMC11040345 DOI: 10.1002/advs.202306915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/10/2024] [Indexed: 02/16/2024]
Abstract
Recent studies suggest that circular RNA (circRNA)-mediated post-translational modification of RNA-binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi-omics approach. Has_circ_0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif-containing 21 to reduce the proteasome-mediated degradation of NCL via K48-linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient-derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi-omics landscape of circRNA-mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target.
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Affiliation(s)
- Xin Hu
- Zhejiang University School of MedicineHangzhou310058China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- NHC Key Laboratory of Combined Multi‐organ TransplantationHangzhou310003China
| | - Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhou310053China
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhou310053China
| | - Qiyang Cheng
- Department of Hepatobiliary SurgeryBeijing Chaoyang Hospital affiliated to Capital Medical UniversityBeijing100020China
| | - Jianyong Zhuo
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Renyi Su
- Zhejiang University School of MedicineHangzhou310058China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
| | - Chiyu He
- Zhejiang University School of MedicineHangzhou310058China
- Department of Hepatobiliary and Pancreatic SurgeryShulan (Hangzhou) HospitalHangzhou310022China
| | - Yichao Wu
- Zhejiang University School of MedicineHangzhou310058China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
| | - Zhikun Liu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Beng Yang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310006China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Lijun Meng
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Shusen Zheng
- NHC Key Laboratory of Combined Multi‐organ TransplantationHangzhou310003China
- Department of Hepatobiliary and Pancreatic SurgeryShulan (Hangzhou) HospitalHangzhou310022China
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310006China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Jiayin Yang
- Department of Liver SurgeryLiver Transplantation CenterWest China Hospital of Sichuan UniversityChengdu332001China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou310006China
| | - Ronggao Chen
- NHC Key Laboratory of Combined Multi‐organ TransplantationHangzhou310003China
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou310006China
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhou310058China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhou310006China
- NHC Key Laboratory of Combined Multi‐organ TransplantationHangzhou310003China
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28
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Zhang W, Huang H, Liu X, Zhang L, Li L, Ding Y, Xiao Y, Ali MJ, Sun H, Xiao C. scRNA-Seq: First Atlas and Cellular Landscape of Lacrimal Sac: Implications in Primary Acquired Nasolacrimal Duct Obstruction Pathogenesis. Invest Ophthalmol Vis Sci 2024; 65:38. [PMID: 38551583 PMCID: PMC10981439 DOI: 10.1167/iovs.65.3.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 03/10/2024] [Indexed: 04/01/2024] Open
Abstract
Purpose The aim of this study was to describe the transcriptional changes of individual cellular components in the lacrimal sac in patients with primary acquired nasolacrimal duct obstruction (PANDO) and attempt to construct the first lacrimal sac cellular atlas to elucidate the potential mechanisms that may drive the disease pathogenesis. Methods Lacrimal sac samples were obtained intra-operatively during the endoscopic dacryocystorhinostomy (EnDCR) procedure from five patients. Single-cell RNA sequencing was performed to analyze each individual cell population including epithelial and immune cells during the early inflammatory and late inflammatory phases of the disease. Results Eleven cell types were identified among 25,791 cells. T cells and B cells were the cell populations with the greatest variation in cell numbers between the two phases and were involved in immune response and epithelium migration-related pathways. The present study showed that epithelial cells highly expressed the genes of senescence-associated secretory phenotype (SASP) and were involved in influencing the inflammation, neutrophil chemotaxis, and migration during the late inflammatory stage. Enhanced activity of CXCLs-CXCRs between the epithelial cells and neutrophils was noted by the cell-cell communication analysis and is suspected to play a role in inflammation by recruiting more neutrophils. Conclusions The study presents a comprehensive single-cell landscape of the lacrimal sac cells in different phases of PANDO. The contribution of T cells, B cells, and epithelial cells to the inflammatory response, and construction of the intercellular signaling networks between the cells within the lacrimal sac has further enhanced the present understanding of the PANDO pathogenesis.
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Affiliation(s)
- Wenyue Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Huan Huang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xueru Liu
- Ophthalmic Center, Xinjiang 474 Hospital, Urumqi, Xinjiang, China
| | - Leilei Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Lunhao Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Yi Ding
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Mohammad Javed Ali
- Govindram Seksaria Institute of Dacryology, L.V. Prasad Eye Institute, Hyderabad, India
| | - Hao Sun
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Caiwen Xiao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
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Dzhumashev D, Anton-Joseph S, Morel VJ, Timpanaro A, Bordon G, Piccand C, Aleandri S, Luciani P, Rössler J, Bernasconi M. Rapid liposomal formulation for nucleolin targeting to rhabdomyosarcoma cells. Eur J Pharm Biopharm 2024; 194:49-61. [PMID: 38029941 DOI: 10.1016/j.ejpb.2023.11.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/01/2023]
Abstract
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations.
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Affiliation(s)
- Dzhangar Dzhumashev
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Stenija Anton-Joseph
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Victoria J Morel
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Andrea Timpanaro
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Gregor Bordon
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Caroline Piccand
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Simone Aleandri
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Paola Luciani
- Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Jochen Rössler
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Michele Bernasconi
- Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland.
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30
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Lim DY, Hwang BH. Aptamer-modified tetrahedral DNA nanostructure-immobilized liposome for specific gene delivery and potential cancer theragnostic. Biotechnol J 2024; 19:e2300156. [PMID: 37837335 DOI: 10.1002/biot.202300156] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 09/19/2023] [Accepted: 10/11/2023] [Indexed: 10/16/2023]
Abstract
Targeted delivery of therapeutic agents to cancer cells is crucial for effective cancer treatment without adverse effects. In this study, we developed a novel delivery carrier, Aptamer-modified tetrahedral DNA nanostructure (TDN) immobilized Liposome (ApTL), for specific delivery to nucleolin-overexpressing cancer cells. We demonstrated that targeted ApTL was highly effective in delivering plasmid and mRNA to nucleolin-overexpressing cancer cells compared to non-targeted ApTL with a non-specific aptamer. ApTL, which is highly negative and nano-sized, specifically delivered nucleic acids to MDA-MB-231 and HeLa cancer cells, primarily via lipid-raft-mediated endocytosis. Furthermore, the co-delivery of mRNA and doxorubicin resulted in increased apoptosis and reduced cancer cell viability. Interestingly, co-delivery of mRNA and Dox did not show a significant difference in EGFP expression at 24 h but dramatically increased EGFP expression at 48 h, making ApTL/mEGFP/Dox a promising candidate for detecting live cancer cells after targeted cancer drug treatment. Our results suggest that ApTL can be a promising tool for the targeted delivery of therapeutic agents to nucleolin-overexpressing cancer cells, providing a new strategy for cancer theragnostic.
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Affiliation(s)
- Doo Young Lim
- Department of Bioengineering and Nano-bioengineering, Incheon National University, Incheon, South Korea
| | - Byeong Hee Hwang
- Department of Bioengineering and Nano-bioengineering, Incheon National University, Incheon, South Korea
- Division of Bioengineering, Incheon National University, Incheon, South Korea
- Research Center for Bio Material & Process Development, Incheon National University, Incheon, Republic of Korea
- Institute for New Drug Development, Incheon National University, Incheon, South Korea
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31
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Wang D, Hou L, Ji Y, Xie J, Zhao J, Zhu N, Yang X, Zhou J, Cui Y, Guo J, Feng X, Liu J. Ubiquitination-dependent degradation of nucleolin mediated by porcine circovirus type 3 capsid protein. J Virol 2023; 97:e0089423. [PMID: 38032196 PMCID: PMC10734473 DOI: 10.1128/jvi.00894-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/27/2023] [Indexed: 12/01/2023] Open
Abstract
IMPORTANCE Porcine circovirus type 3 (PCV3) is an emerging pathogen that causes multisystem disease in pigs and poses a severe threat to the swine industry. However, the mechanisms of how PCV3 uses host proteins to regulate its own life cycle are not well understood. In this study, we found that PCV3 capsid protein interacts with nucleolin and degrades it. Degradation of nucleolin by the PCV3 capsid protein requires recruitment of the enzyme RNF34, which is transported to the nucleolus from the cytoplasm in the presence of the PCV3 capsid protein. Nucleolin also decreases PCV3 replication by promoting the release of interferon β. These findings clarify the mechanism by which nucleolin modulates PCV3 replication in cells, thereby facilitating to provide an important strategy for preventing and controlling PCV3 infection.
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Affiliation(s)
- Dedong Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Lei Hou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Ying Ji
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jiali Xie
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jie Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Ning Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Xiaoyu Yang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jianwei Zhou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Yongqiu Cui
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jinshuo Guo
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Xufei Feng
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jue Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
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Montoya-Gómez A, Tonello F, Spolaore B, Massimino ML, Montealegre-Sánchez L, Castillo A, Rivera Franco N, Sevilla-Sánchez MJ, Solano-Redondo LM, Mosquera-Escudero M, Jiménez-Charris E. Pllans-II: Unveiling the Action Mechanism of a Promising Chemotherapeutic Agent Targeting Cervical Cancer Cell Adhesion and Survival Pathways. Cells 2023; 12:2715. [PMID: 38067143 PMCID: PMC10705806 DOI: 10.3390/cells12232715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 10/12/2023] [Accepted: 10/18/2023] [Indexed: 12/18/2023] Open
Abstract
Despite advances in chemotherapeutic drugs used against cervical cancer, available chemotherapy treatments adversely affect the patient's quality of life. For this reason, new molecules from natural sources with antitumor potential and few side effects are required. In previous research, Pllans-II, a phospholipase A2 type-Asp49 from Porthidium lansbergii lansbergii snake venom, has shown selective attack against the HeLa and Ca Ski cervical cancer cell lines. This work suggests that the cytotoxic effect generated by Pllans-II on HeLa cells is triggered without affecting the integrity of the cytoplasmic membrane or depolarizing the mitochondrial membranes. The results allow us to establish that cell death in HeLa is related to the junction blockage between α5β1 integrins and fibronectin of the extracellular matrix. Pllans-II reduces the cells' ability of adhesion and affects survival and proliferation pathways mediated by intracellular communication with the external environment. Our findings confirmed Pllans-II as a potential prototype for developing a selective chemotherapeutic drug against cervical cancer.
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Affiliation(s)
- Alejandro Montoya-Gómez
- Grupo de Nutrición, Facultad de Salud, Universidad del Valle, Cali 760043, Colombia; (L.M.-S.); (M.J.S.-S.); (L.M.S.-R.); (M.M.-E.)
| | - Fiorella Tonello
- Istituto di Neuroscienze, CNR, Via Ugo Bassi 58/B, 35131 Padova, Italy; (F.T.); (M.L.M.)
| | - Barbara Spolaore
- Dipartimento di Scienze del Farmaco, Università di Padova, Via F. Marzolo 5, 35131 Padova, Italy;
| | - Maria Lina Massimino
- Istituto di Neuroscienze, CNR, Via Ugo Bassi 58/B, 35131 Padova, Italy; (F.T.); (M.L.M.)
| | - Leonel Montealegre-Sánchez
- Grupo de Nutrición, Facultad de Salud, Universidad del Valle, Cali 760043, Colombia; (L.M.-S.); (M.J.S.-S.); (L.M.S.-R.); (M.M.-E.)
- Grupo de Investigación en Ingeniería Biomédica-GBIO, Universidad Autónoma de Occidente, Cali 760030, Colombia
| | - Andrés Castillo
- TAO-Lab, Centre for Bioinformatics and Photonics-CIBioFi, Department of Biology, Universidad del Valle, Cali 760032, Colombia; (A.C.); (N.R.F.)
| | - Nelson Rivera Franco
- TAO-Lab, Centre for Bioinformatics and Photonics-CIBioFi, Department of Biology, Universidad del Valle, Cali 760032, Colombia; (A.C.); (N.R.F.)
| | - María José Sevilla-Sánchez
- Grupo de Nutrición, Facultad de Salud, Universidad del Valle, Cali 760043, Colombia; (L.M.-S.); (M.J.S.-S.); (L.M.S.-R.); (M.M.-E.)
| | - Luis Manuel Solano-Redondo
- Grupo de Nutrición, Facultad de Salud, Universidad del Valle, Cali 760043, Colombia; (L.M.-S.); (M.J.S.-S.); (L.M.S.-R.); (M.M.-E.)
| | - Mildrey Mosquera-Escudero
- Grupo de Nutrición, Facultad de Salud, Universidad del Valle, Cali 760043, Colombia; (L.M.-S.); (M.J.S.-S.); (L.M.S.-R.); (M.M.-E.)
| | - Eliécer Jiménez-Charris
- Grupo de Nutrición, Facultad de Salud, Universidad del Valle, Cali 760043, Colombia; (L.M.-S.); (M.J.S.-S.); (L.M.S.-R.); (M.M.-E.)
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33
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Zou K, Wang S, Wang Z, Zou H, Yang F. Dual-Signal Feature Spaces Map Protein Subcellular Locations Based on Immunohistochemistry Image and Protein Sequence. SENSORS (BASEL, SWITZERLAND) 2023; 23:9014. [PMID: 38005402 PMCID: PMC10675401 DOI: 10.3390/s23229014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 10/29/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023]
Abstract
Protein is one of the primary biochemical macromolecular regulators in the compartmental cellular structure, and the subcellular locations of proteins can therefore provide information on the function of subcellular structures and physiological environments. Recently, data-driven systems have been developed to predict the subcellular location of proteins based on protein sequence, immunohistochemistry (IHC) images, or immunofluorescence (IF) images. However, the research on the fusion of multiple protein signals has received little attention. In this study, we developed a dual-signal computational protocol by incorporating IHC images into protein sequences to learn protein subcellular localization. Three major steps can be summarized as follows in this protocol: first, a benchmark database that includes 281 proteins sorted out from 4722 proteins of the Human Protein Atlas (HPA) and Swiss-Prot database, which is involved in the endoplasmic reticulum (ER), Golgi apparatus, cytosol, and nucleoplasm; second, discriminative feature operators were first employed to quantitate protein image-sequence samples that include IHC images and protein sequence; finally, the feature subspace of different protein signals is absorbed to construct multiple sub-classifiers via dimensionality reduction and binary relevance (BR), and multiple confidence derived from multiple sub-classifiers is adopted to decide subcellular location by the centralized voting mechanism at the decision layer. The experimental results indicated that the dual-signal model embedded IHC images and protein sequences outperformed the single-signal models with accuracy, precision, and recall of 75.41%, 80.38%, and 74.38%, respectively. It is enlightening for further research on protein subcellular location prediction under multi-signal fusion of protein.
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Affiliation(s)
- Kai Zou
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang 330038, China
- School of Computer Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Simeng Wang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang 330038, China
| | - Ziqian Wang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang 330038, China
| | - Hongliang Zou
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang 330038, China
| | - Fan Yang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang 330038, China
- Artificial Intelligence and Bioinformation Cognition Laboratory, Jiangxi Science and Technology Normal University, Nanchang 330038, China
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34
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Unida V, Mangano E, Camboni T, Consolandi C, Desideri A, Severgnini M, Cifola I, Biocca S. Insights on the molecular mechanisms of cytotoxicity induced by AS1411 linked to folate-functionalized DNA nanocages in cancer cells. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2023; 54:102710. [PMID: 37734452 DOI: 10.1016/j.nano.2023.102710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/28/2023] [Accepted: 08/31/2023] [Indexed: 09/23/2023]
Abstract
Self-assembled multivalent DNA nanocages are an emerging class of molecules useful for biomedicine applications. Here, we investigated the molecular mechanisms of cytotoxicity induced by AS1411 free aptamer, AS1411-linked nanocages (Apt-NCs) and nanocages harboring both folate and AS1411 functionalization (Fol-Apt-NCs) in HeLa and MDA-MB-231 cancer cell lines. The three treatments showed different cytotoxic efficacy and Fol-Apt-NCs resulted the most effective in inhibiting cell proliferation and inducing apoptotic pathways and ROS activation in both HeLa and MDA-MB-231 cells. RNA-seq analysis allowed to identify biological functions and genes altered by the various treatments, depending on the AS1411 route of intracellular entry, highlighting the different behavior of the two cancer cell lines. Notably, Fol-Apt-NCs altered the expression of a subset of genes associated to cancer chemoresistance in MDA-MB-231, but not in HeLa cells, and this may explain the increased chemosensitivity to drugs delivered through DNA nanocages of the triple-negative breast cancer cells.
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Affiliation(s)
- Valeria Unida
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
| | - Eleonora Mangano
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), via F.lli Cervi 93, 20054 Segrate, Milan, Italy.
| | - Tania Camboni
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), via F.lli Cervi 93, 20054 Segrate, Milan, Italy.
| | - Clarissa Consolandi
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), via F.lli Cervi 93, 20054 Segrate, Milan, Italy.
| | - Alessandro Desideri
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy.
| | - Marco Severgnini
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), via F.lli Cervi 93, 20054 Segrate, Milan, Italy.
| | - Ingrid Cifola
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), via F.lli Cervi 93, 20054 Segrate, Milan, Italy.
| | - Silvia Biocca
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
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35
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Kumar C, Mylavarapu SVS. Nucleolin is required for multiple centrosome-associated functions in early vertebrate mitosis. Chromosoma 2023; 132:305-315. [PMID: 37615728 DOI: 10.1007/s00412-023-00808-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 06/10/2023] [Accepted: 08/11/2023] [Indexed: 08/25/2023]
Abstract
Nucleolin is a multifunctional RNA-binding protein that resides predominantly not only in the nucleolus, but also in multiple other subcellular pools in the cytoplasm in mammalian cells, and is best known for its roles in ribosome biogenesis, RNA stability, and translation. During early mitosis, nucleolin is required for equatorial mitotic chromosome alignment prior to metaphase. Using high resolution fluorescence imaging, we reveal that nucleolin is required for multiple centrosome-associated functions at the G2-prophase boundary. Nucleolin depletion led to dissociation of the centrosomes from the G2 nuclear envelope, a delay in the onset of nuclear envelope breakdown, reduced inter-centrosome separation, and longer metaphase spindles. Our results reveal novel roles for nucleolin in early mammalian mitosis, establishing multiple important functions for nucleolin during mammalian cell division.
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Affiliation(s)
- Chandan Kumar
- Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, -121001, India
| | - Sivaram V S Mylavarapu
- Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, -121001, India.
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Abeesh P, Bouvet P, Guruvayoorappan C. AS1411 aptamer tagged PEGylated liposomes as a smart nanocarrier for tumor-specific delivery of Withaferin A for mitigating pulmonary metastasis. BIOMATERIALS ADVANCES 2023; 154:213661. [PMID: 37879185 DOI: 10.1016/j.bioadv.2023.213661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/17/2023] [Accepted: 10/12/2023] [Indexed: 10/27/2023]
Abstract
Metastasis is the most challenging health problem contributing to about 90 % of cancer-related deaths worldwide. Metastatic tumors are highly aggressive and resistant to the most available therapeutic options. Hence, innovative therapeutic approaches are required to target metastatic tumors selectively. In this study, we prepared AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes (ALW) and investigated its therapeutic effect in B16F10 induced in pulmonary metastasis mice models. The prepared formulations' size and morphological properties were evaluated using dynamic light scattering system and Transmission electron microscope. ALW had spherical-shaped nanosized particles with a size of 118 nm and an encapsulation efficacy of 82.5 %. TEM analysis data indicated that ALW has excellent dispersibility and uniform spherical nano-size particles. ALW inhibited cell viability, and induced cell apoptosis of B16F10. In vivo, the pulmonary metastasis study in C57BL/6 mice revealed that the ALW significantly (p < 0.01) improved the encapsulated WA anti-metastatic activity and survival rate compared to WA or LW treated groups. ALW significantly (p < 0.01) downregulated the levels of IL-6, TNF-α, and IL-1β and significantly reduced the lung collagen hydroxyproline, hexosamine, and uronic acid content in metastatic tumor bearing animals compared to WA or LW. Gene expression levels of MMPs and NF-κB were downregulated in ALW treated metastatic pulmonary tumor-bearing mice. These findings demonstrate that the AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes could be a promising nanoliposomal formulation for targeting metastatic tumors.
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Affiliation(s)
- Prathapan Abeesh
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College post, Thiruvananthapuram 695011, Kerala, India (Recognized Research Centre, University of Kerala)
| | - Phillipe Bouvet
- Centre de Recherche en Cancerologie de Lyon, Universite de Lyon 1, Inserm U1052, CNRS UMR5286 Centre Leon Berard, CEDEX 08, F-69373 Lyon, France; Ecole Normale Superieur de Lyon, Universite de Lyon 1, F-69007 Lyon, France
| | - Chandrasekaran Guruvayoorappan
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College post, Thiruvananthapuram 695011, Kerala, India (Recognized Research Centre, University of Kerala).
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37
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Chen S, Zhou Y, Peng P, Xu L, Tang Q, Chen W, Gu W. SNHG15-Mediated Localization of Nucleolin at the Cell Protrusions Regulates CDH2 mRNA Expression and Cell Invasion. Int J Mol Sci 2023; 24:15600. [PMID: 37958584 PMCID: PMC10650932 DOI: 10.3390/ijms242115600] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/15/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
LncRNAs are emerging as important regulators of gene expression by controlling transcription in the nucleus and by modulating mRNA translation in the cytoplasm. In this study, we reveal a novel function of lncRNA SNHG15 in mediating breast cancer cell invasion through regulating the local translation of CDH2 mRNA. We show that SNHG15 preferentially localizes at the cellular protrusions or cell leading edge and that this localization is directed by IMP1, a multifunctional protein involved in many aspects of RNA regulation. We demonstrate that SNHG15 also forms a complex with nucleolin, allowing nucleolin to be co-transported with SNHG15 to the cell protrusions, where the accumulated nucleolin is able to bind to CDH2 mRNA. Interaction with nucleolin stabilizes local CDH2 mRNA and regulates its translation, thus promoting cell invasive potential. Our findings reveal an underlying mechanism by which lncRNA could serve as a carrier to transport a protein regulator into a specific cell compartment to enhance target mRNA expression.
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Affiliation(s)
| | | | | | | | | | | | - Wei Gu
- Key Immunopathology Laboratory of Guangdong Province, Department of Pathophysiology, Shantou University Medical College, Shantou 515041, China; (S.C.); (Y.Z.); (P.P.); (L.X.); (Q.T.); (W.C.)
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38
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Zhang X, Zhang P, Xiao C, Chen X. ROS-Responsive Self-Degradable DNA Nanogels for Targeted Anticancer Drug Delivery. ACS Macro Lett 2023; 12:1317-1323. [PMID: 37713132 DOI: 10.1021/acsmacrolett.3c00442] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
Here, a reactive oxygen species (ROS)-responsive targeted anticancer drug delivery system was developed by embedding a nitrophenyl tetramethyl-dioxaborolanyl benzyl carbamate (NBC)-modified deoxyribonuclease I (DNase I) in a DNase-degradable aptamer-based DNA nanogel. The DNA nanogel was formed by hybridization of three types of building blocks, namely, Y-shaped monomer 1 with three sticky ends, Y-shaped monomer 2 with two sticky ends and an aptamer end, and a DNA linker with two sticky ends. Single doxorubicin (DOX) or ribonuclease A (RNase A) as well as the combination of DOX and RNase A were effectively loaded into the nanogels, wherein DOX was embedded into DNA skeleton, while RNase A was encapsulated into nanogel matrix. The blocked enzymatic activity of DNase I due to NBC modification could be restored upon intracellular ROS-triggered NBC deprotection, resulting in self-degradation of the nanogels to release both DOX and RNase A. Consequently, the DOX and RNase A coloaded nanogels significantly inhibited the proliferation of MCF-7 cells through a synergistic effect. To sum up, this DNA-based drug delivery system with ROS-responsive self-degradation properties should be promising for application in targeted and synergistic cancer therapy.
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Affiliation(s)
- Xiaonong Zhang
- Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Peng Zhang
- Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, P. R. China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
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39
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Wolfová K, Otevřelová P, Holoubek A, Brodská B. Nucleolar phosphoprotein modifications as a marker of apoptosis induced by RITA treatment. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119501. [PMID: 37276927 DOI: 10.1016/j.bbamcr.2023.119501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/19/2023] [Accepted: 05/21/2023] [Indexed: 06/07/2023]
Abstract
Reactivating p53 and Inducing Tumor Apoptosis (RITA) has been reported to increase the p53 activity and to trigger p53-dependent apoptosis in cancer cells with wild-type p53. Tumor suppressor p53 interacts with nucleolar phosphoproteins nucleophosmin (NPM) and nucleolin (NCL), which have crucial role in many cellular processes. Specific NPM mutations associated with acute myeloid leukemia (AML) cause aberrant localization of NPM and p53 in the cytoplasm with possible impact on the p53 function. We tested an effect of RITA on primary cells, and we found significant RITA-induced changes in NPM and NCL phosphorylation associated with apoptosis in cells of AML patients, but not that of healthy donors. Subsequent screening of several AML cell lines revealed heterogeneous response to RITA, and confirmed an association of the specific phosphorylation with apoptosis. While decreased NCL phosphorylation at Threonines T76 and T84 could be attributed to RITA-induced cell cycle arrest, enhanced NPM phosphorylation at Threonine T199 was not accompanied by the cell cycle changes and it correlated with sensitivity to RITA. Simultaneously, inverse changes occurred at Serine S4 of the NPM. These new findings of RITA mechanism of action could establish the NPM pT199/pS4 ratio as a marker for suitability of RITA treatment of AML cells.
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Affiliation(s)
- Kateřina Wolfová
- Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12820 Prague 2, Czech Republic
| | - Petra Otevřelová
- Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12820 Prague 2, Czech Republic
| | - Aleš Holoubek
- Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12820 Prague 2, Czech Republic
| | - Barbora Brodská
- Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 12820 Prague 2, Czech Republic.
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40
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Xiao CD, Zhong MQ, Gao Y, Yang ZL, Jia MH, Hu XH, Xu Y, Shen XC. A Unique G-Quadruplex Aptamer: A Novel Approach for Cancer Cell Recognition, Cell Membrane Visualization, and RSV Infection Detection. Int J Mol Sci 2023; 24:14344. [PMID: 37762645 PMCID: PMC10531985 DOI: 10.3390/ijms241814344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Surface staining has emerged as a rapid technique for applying external stains to trace cellular identities in diverse populations. In this study, we developed a distinctive aptamer with selective binding to cell surface nucleolin (NCL), bypassing cytoplasmic internalization. Conjugation of the aptamer with a FAM group facilitated NCL visualization on live cell surfaces with laser confocal microscopy. To validate the aptamer-NCL interaction, we employed various methods, including the surface plasmon resonance, IHC-based flow cytometry, and electrophoretic mobility shift assay. The G-quadruplex formations created by aptamers were confirmed with a nuclear magnetic resonance and an electrophoretic mobility shift assay utilizing BG4, a G-quadruplex-specific antibody. Furthermore, the aptamer exhibited discriminatory potential in distinguishing between cancerous and normal cells using flow cytometry. Notably, it functioned as a dynamic probe, allowing real-time monitoring of heightened NCL expression triggered by a respiratory syncytial virus (RSV) on normal cell surfaces. This effect was subsequently counteracted with dsRNA transfection and suppressed the NCL expression; thus, emphasizing the dynamic attributes of the probe. These collective findings highlight the robust versatility of our aptamer as a powerful tool for imaging cell surfaces, holding promising implications for cancer cell identification and the detection of RSV infections.
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Affiliation(s)
- Chao-Da Xiao
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China
| | - Ming-Qing Zhong
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China
| | - Yue Gao
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
| | - Zheng-Lin Yang
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
| | - Meng-Hao Jia
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
| | - Xiao-Hui Hu
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
| | - Yan Xu
- Division of Chemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan;
| | - Xiang-Chun Shen
- State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; (M.-Q.Z.); (Y.G.); (Z.-L.Y.); (M.-H.J.); (X.-H.H.)
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China
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41
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Davodabadi F, Mirinejad S, Fathi-Karkan S, Majidpour M, Ajalli N, Sheervalilou R, Sargazi S, Rozmus D, Rahdar A, Diez-Pascual AM. Aptamer-functionalized quantum dots as theranostic nanotools against cancer and bacterial infections: A comprehensive overview of recent trends. Biotechnol Prog 2023; 39:e3366. [PMID: 37222166 DOI: 10.1002/btpr.3366] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/21/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023]
Abstract
Aptamers (Apts) are synthetic nucleic acid ligands that can be engineered to target various molecules, including amino acids, proteins, and pharmaceuticals. Through a series of adsorption, recovery, and amplification steps, Apts are extracted from combinatorial libraries of synthesized nucleic acids. Using aptasensors in bioanalysis and biomedicine can be improved by combining them with nanomaterials. Moreover, Apt-associated nanomaterials, including liposomes, polymeric, dendrimers, carbon nanomaterials, silica, nanorods, magnetic NPs, and quantum dots (QDs), have been widely used as promising nanotools in biomedicine. Following surface modifications and conjugation with appropriate functional groups, these nanomaterials can be successfully used in aptasensing. Advanced biological assays can use Apts immobilized on QD surfaces through physical interaction and chemical bonding. Accordingly, modern QD aptasensing platforms rely on interactions between QDs, Apts, and targets to detect them. QD-Apt conjugates can be used to directly detect prostate, ovarian, colorectal, and lung cancers or simultaneously detect biomarkers associated with these malignancies. Tenascin-C, mucin 1, prostate-specific antigen, prostate-specific membrane antigen, nucleolin, growth factors, and exosomes are among the cancer biomarkers that can be sensitively detected using such bioconjugates. Furthermore, Apt-conjugated QDs have shown great potential for controlling bacterial infections such as Bacillus thuringiensis, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Campylobacter jejuni, Staphylococcus aureus, and Salmonella typhimurium. This comprehensive review discusses recent advancements in the design of QD-Apt bioconjugates and their applications in cancer and bacterial theranostics.
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Affiliation(s)
- Fatemeh Davodabadi
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran
| | - Shekoufeh Mirinejad
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Sonia Fathi-Karkan
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mahdi Majidpour
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Narges Ajalli
- Department of Chemical Engineering, Faculty of Engineering, University of Tehran, Tehran, Iran
| | | | - Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Dominika Rozmus
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol, Iran
| | - Ana M Diez-Pascual
- Universidad de Alcalá, Facultad de Ciencias, Departamento de Quimica Analitica, Quimica Fisica e Ingenieria Quimica, Madrid, Spain
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Thongchot S, Aksonnam K, Thuwajit P, Yenchitsomanus PT, Thuwajit C. Nucleolin‑based targeting strategies in cancer treatment: Focus on cancer immunotherapy (Review). Int J Mol Med 2023; 52:81. [PMID: 37477132 PMCID: PMC10555485 DOI: 10.3892/ijmm.2023.5284] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/15/2023] [Indexed: 07/22/2023] Open
Abstract
The benefits of treating several types of cancers using immunotherapy have recently been established. The overexpression of nucleolin (NCL) in a number of types of cancer provides an attractive antigen target for the development of novel anticancer immunotherapeutic treatments. NCL is a multifunctional protein abundantly distributed in the nucleus, cytoplasm and cell membrane. It influences carcinogenesis, and the proliferation, survival and metastasis of cancer cells, leading to cancer progression. Additionally, the meta‑analysis of total and cytoplasmic NCL overexpression indicates a poor prognosis of patients with breast cancer. The AS1411 aptamers currently appear to have therapeutic action in the phase II clinical trial. The authors' research group has recently explored the anticancer function of NCL through the activation of T cells by dendritic cell‑based immunotherapy. The present review describes and discusses the mechanisms through which the multiple functions of NCL can participate in the progression of cancer. In addition, the studies that define the utility of NCL‑dependent anticancer therapies are summarized, with specific focus being paid to cancer immunotherapeutic approaches.
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Affiliation(s)
- Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University
| | - Krittaya Aksonnam
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University
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Zou K, Wang S, Wang Z, Zhang Z, Yang F. HAR_Locator: a novel protein subcellular location prediction model of immunohistochemistry images based on hybrid attention modules and residual units. Front Mol Biosci 2023; 10:1171429. [PMID: 37664182 PMCID: PMC10470064 DOI: 10.3389/fmolb.2023.1171429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 08/04/2023] [Indexed: 09/05/2023] Open
Abstract
Introduction: Proteins located in subcellular compartments have played an indispensable role in the physiological function of eukaryotic organisms. The pattern of protein subcellular localization is conducive to understanding the mechanism and function of proteins, contributing to investigating pathological changes of cells, and providing technical support for targeted drug research on human diseases. Automated systems based on featurization or representation learning and classifier design have attracted interest in predicting the subcellular location of proteins due to a considerable rise in proteins. However, large-scale, fine-grained protein microscopic images are prone to trapping and losing feature information in the general deep learning models, and the shallow features derived from statistical methods have weak supervision abilities. Methods: In this work, a novel model called HAR_Locator was developed to predict the subcellular location of proteins by concatenating multi-view abstract features and shallow features, whose advanced advantages are summarized in the following three protocols. Firstly, to get discriminative abstract feature information on protein subcellular location, an abstract feature extractor called HARnet based on Hybrid Attention modules and Residual units was proposed to relieve gradient dispersion and focus on protein-target regions. Secondly, it not only improves the supervision ability of image information but also enhances the generalization ability of the HAR_Locator through concatenating abstract features and shallow features. Finally, a multi-category multi-classifier decision system based on an Artificial Neural Network (ANN) was introduced to obtain the final output results of samples by fitting the most representative result from five subset predictors. Results: To evaluate the model, a collection of 6,778 immunohistochemistry (IHC) images from the Human Protein Atlas (HPA) database was used to present experimental results, and the accuracy, precision, and recall evaluation indicators were significantly increased to 84.73%, 84.77%, and 84.70%, respectively, compared with baseline predictors.
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Affiliation(s)
- Kai Zou
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang, China
| | - Simeng Wang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang, China
| | - Ziqian Wang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang, China
| | - Zhihai Zhang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang, China
| | - Fan Yang
- School of Communications and Electronics, Jiangxi Science and Technology Normal University, Nanchang, China
- Artificial Intelligence and Bioinformation Cognition Laboratory, Jiangxi Science and Technology Normal University, Nanchang, China
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Fan D, Cao Y, Cao M, Wang Y, Cao Y, Gong T. Nanomedicine in cancer therapy. Signal Transduct Target Ther 2023; 8:293. [PMID: 37544972 PMCID: PMC10404590 DOI: 10.1038/s41392-023-01536-y] [Citation(s) in RCA: 217] [Impact Index Per Article: 108.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 05/31/2023] [Accepted: 06/04/2023] [Indexed: 08/08/2023] Open
Abstract
Cancer remains a highly lethal disease in the world. Currently, either conventional cancer therapies or modern immunotherapies are non-tumor-targeted therapeutic approaches that cannot accurately distinguish malignant cells from healthy ones, giving rise to multiple undesired side effects. Recent advances in nanotechnology, accompanied by our growing understanding of cancer biology and nano-bio interactions, have led to the development of a series of nanocarriers, which aim to improve the therapeutic efficacy while reducing off-target toxicity of the encapsulated anticancer agents through tumor tissue-, cell-, or organelle-specific targeting. However, the vast majority of nanocarriers do not possess hierarchical targeting capability, and their therapeutic indices are often compromised by either poor tumor accumulation, inefficient cellular internalization, or inaccurate subcellular localization. This Review outlines current and prospective strategies in the design of tumor tissue-, cell-, and organelle-targeted cancer nanomedicines, and highlights the latest progress in hierarchical targeting technologies that can dynamically integrate these three different stages of static tumor targeting to maximize therapeutic outcomes. Finally, we briefly discuss the current challenges and future opportunities for the clinical translation of cancer nanomedicines.
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Affiliation(s)
- Dahua Fan
- Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, 528300, China.
- Department of Neurology, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.
| | - Yongkai Cao
- Department of Neurology, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China
| | - Meiqun Cao
- Department of Neurology, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China
| | - Yajun Wang
- Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, 528300, China
| | | | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
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Nel J, Elkhoury K, Velot É, Bianchi A, Acherar S, Francius G, Tamayol A, Grandemange S, Arab-Tehrany E. Functionalized liposomes for targeted breast cancer drug delivery. Bioact Mater 2023; 24:401-437. [PMID: 36632508 PMCID: PMC9812688 DOI: 10.1016/j.bioactmat.2022.12.027] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/05/2022] [Accepted: 12/25/2022] [Indexed: 01/03/2023] Open
Abstract
Despite the exceptional progress in breast cancer pathogenesis, prognosis, diagnosis, and treatment strategies, it remains a prominent cause of female mortality worldwide. Additionally, although chemotherapies are effective, they are associated with critical limitations, most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance (MDR) cancer cells. Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use, none of which employ active targeting. In this review, we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface, transmembrane and internal cell receptors, enzymes, direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells, e.g., cancer stem cells, cells associated with the tumor microenvironment, etc.
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Affiliation(s)
- Janske Nel
- Université de Lorraine, LIBio, F-54000, Nancy, France
| | | | - Émilie Velot
- Université de Lorraine, CNRS, IMoPA, F-54000, Nancy, France
| | - Arnaud Bianchi
- Université de Lorraine, CNRS, IMoPA, F-54000, Nancy, France
| | - Samir Acherar
- Université de Lorraine, CNRS, LCPM, F-54000, Nancy, France
| | | | - Ali Tamayol
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
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Yu X, Xie L, Ge J, Li H, Zhong S, Liu X. Integrating single-cell RNA-seq and spatial transcriptomics reveals MDK-NCL dependent immunosuppressive environment in endometrial carcinoma. Front Immunol 2023; 14:1145300. [PMID: 37081869 PMCID: PMC10110842 DOI: 10.3389/fimmu.2023.1145300] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/24/2023] [Indexed: 04/07/2023] Open
Abstract
ObjectivesThe tumor microenvironment (TME) play important roles in progression of endometrial carcinoma (EC). We aimed to assess the cell populations in TME of EC.MethodsWe downloaded datasets of single-cell RNA-seq (scRNA-seq) and spatial transcriptome (ST) for EC from GEO, and downloaded RNA-Seq (FPKM) and clinical data of TCGA-UCEC project from TCGA. The datasets were analyzed using R software.ResultsWe obtained 5 datasets of scRNA-seq, 1 of ST and 569 samples of RNA-seq. Totally, 0.2 billion transcripts and 33,408 genes were detected in 33,162 cells from scRNA-seq. The cells were classified into 9 clusters, and EC cells were originated from epithelial cells and ciliated cells. Gene set variation analysis (GSVA) indicated that the pathways enriched in the subclusters of epithelial cells and endothelial cells were significantly different, indicating great heterogeneity in EC. Cell-cell communication analyses showed that EC cells emitted the strongest signals, and endothelial cells received more signals than other cells. Further analysis found that subclusters of 1 and 2 of epithelial cells were showed a more malignant phenotype, which may confer malignant phenotype to subcluster of 0 of endothelial cells through MK pathway by MDL-NCL signal. We also analyzed communications between spatial neighbors with ST data and confirmed the findings on MDL-NCL in cell-cell communication. TCGA and GEO analyses indicated that the expression levels of NCL was inversely correlated with ImmuneScore.ConclusionOur study revealed EC cells can confer malignant phenotype to endothelial cells by MDK-NCL signal, and NCL is associated with suppressed immune activity. EC cells may shape TME by inhibiting immune cells and “educating” stromal cells via MDK-NCL signal.
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Affiliation(s)
- Xinnian Yu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Linjun Xie
- Department of Pharmacy, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jianjuan Ge
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Huixin Li
- Department of Gynecology, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University & Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Shanliang Zhong
- Center of Clinical Laboratory Science, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
- *Correspondence: Shanliang Zhong, ; Xiaolin Liu,
| | - Xiaolin Liu
- Office of Ethics Committee, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
- *Correspondence: Shanliang Zhong, ; Xiaolin Liu,
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Băcăiță ES, Rață DM, Cadinoiu AN, Ghizdovăț V, Agop M, Luca AC. Drug Release from Nanoparticles (Polymeric Nanocapsules and Liposomes) Mimed through a Multifractal Tunnelling-Type Effect. Polymers (Basel) 2023; 15:polym15041018. [PMID: 36850302 PMCID: PMC9962169 DOI: 10.3390/polym15041018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/31/2023] [Accepted: 02/10/2023] [Indexed: 02/22/2023] Open
Abstract
The present study analyzes (theoretically and experimentally) a drug release process from nanoparticles (polymeric nanocapsules and liposomes). This process is functionalized on the surface with an aptamer. These types of drug release processes can also be included in cream-type formulations. The obtained cream ensures the active targeting of tumor epithelial cells, in the case of skin cancer, because it can be easily administered to the skin by spreading, thus avoiding side effects caused by the toxicity of the drug to healthy cells, increasing both patient compliance and the effectiveness of the treatment. The process of obtaining these formulations is a simple one, easy to use and highly reproductible. The theoretical model, based on the multifractal tunnel effect within the Scale Relativity Theory, considers the system as a complex one. In this model, complexity is replaced with system multifractality, quantified in physical quantities as multifractal dimensions and multifractal functions. The main advantage of this approach consists in the fact that it allows us to obtain information on system behavior at a microscopic level and to evaluate microscopic characteristics of the system, such as intrinsic transparences of the drug molecules, multifractal constants as indicators of the system's complexity, the frequency of interactions within the system and the energy ratio between potential barrier energy and the energy of drug molecules.
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Affiliation(s)
- Elena Simona Băcăiță
- Faculty of Machine Manufacturing and Industrial Management, Gheorghe Asachi Technical University of Iasi, D. Mangeron Bld. No. 73, 700050 Iasi, Romania
| | - Delia Mihaela Rață
- Faculty of Medical Dentistry, “Apollonia” University of Iasi, Muzicii Street No. 2, 700511 Iasi, Romania
| | - Anca Niculina Cadinoiu
- Faculty of Medical Dentistry, “Apollonia” University of Iasi, Muzicii Street No. 2, 700511 Iasi, Romania
- Correspondence: (A.N.C.); (M.A.)
| | - Vlad Ghizdovăț
- Department of Biophysics and Medical Physics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Maricel Agop
- Faculty of Machine Manufacturing and Industrial Management, Gheorghe Asachi Technical University of Iasi, D. Mangeron Bld. No. 73, 700050 Iasi, Romania
- Academy of Romanian Scientists, Splaiul Independentei Street No. 54, 050094 Bucharest, Romania
- Correspondence: (A.N.C.); (M.A.)
| | - Alina-Costina Luca
- Department of Mother and Child Medicine-Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
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Gao Y, Cao H, Huang D, Zheng L, Nie Z, Zhang S. RNA-Binding Proteins in Bladder Cancer. Cancers (Basel) 2023; 15:cancers15041150. [PMID: 36831493 PMCID: PMC9953953 DOI: 10.3390/cancers15041150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/09/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
RNA-binding proteins (RBPs) are key regulators of transcription and translation, with highly dynamic spatio-temporal regulation. They are usually involved in the regulation of RNA splicing, polyadenylation, and mRNA stability and mediate processes such as mRNA localization and translation, thereby affecting the RNA life cycle and causing the production of abnormal protein phenotypes that lead to tumorigenesis and development. Accumulating evidence supports that RBPs play critical roles in vital life processes, such as bladder cancer initiation, progression, metastasis, and drug resistance. Uncovering the regulatory mechanisms of RBPs in bladder cancer is aimed at addressing the occurrence and progression of bladder cancer and finding new therapies for cancer treatment. This article reviews the effects and mechanisms of several RBPs on bladder cancer and summarizes the different types of RBPs involved in the progression of bladder cancer and the potential molecular mechanisms by which they are regulated, with a view to providing information for basic and clinical researchers.
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Wei ZL, Juan W, Tong D, Juan LX, Sa LY, Jie HFM, Xiao G, Xiang LG, Jie HM, Xu C. Curcumol inhibits breast cancer growth via NCL/ERα36 and the PI3K/AKT pathway. Food Funct 2023; 14:874-885. [PMID: 36537297 DOI: 10.1039/d2fo02387c] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: Breast cancer (BC) is the most common malignancy worldwide. ERα36 (ERα66 variant) is expressed in many breast cancer cells, especially highly expressed in tamoxifen (TAM)-resistant cell lines and triple-negative breast cancer, and our previous work revealed that nucleolin (NCL) is a protein target of curcumol. This study is aimed at investigating the effect and mechanism of curcumol on ERα36 positive breast cancer cells, and the relationship between curcumol's target protein NCL and ERα36. Study design: Application of in vivo and in vitro studies to reveal the mechanism of curcumol in inhibiting BC growth and the relationship between curcumol's target protein NCL and ERα36. Methods: The anti-tumor effect of curcumol was quantified via an MTT assay, colony formation and cycle arrest, respectively. The expressions of ERα36, NCL and the proteins involved in PI3K/AKT signaling were evaluated by western blotting. The interaction between two proteins was detected using co-immunoprecipitation (Co-IP) and an immunofluorescence assay. A mouse xenograft model was established to verify the role of ERα36 in breast cancer cells and curcumol's effect on ERα36 positive cancer cells. Results: Curcumol inhibited the cell growth, caused cell cycle arrest, decreased cell cycle related proteins and inactivated the PI3K/AKT pathway in ERα36 positive breast cancer cells. There is a positive correlation between NCL and ERα36 in breast cancer cells. In addition, ERα36 bound to NCL; the two proteins were distributed in the nucleus, cytoplasm and plasma membrane, where their expression was obviously decreased by curcumol. Moreover, NCL silenced by NCL siRNA blocked the cell cycle progress and inhibited the activation of PI3K/AKT in MDA-MB-231 cells, while overexpressed ERα36 increased the expression of NCL, promoted the cell cycle progress and enhanced the activity of PI3K/AKT in MCF-7 cells. NCL knockdown or ERα36 overexpression attenuated the effect of curcumol on breast cancer cells. Conclusion: Curcumol reduced the proliferation of breast cancer cells by targeting NCL/ERα36 and inactivating the PI3K/AKT pathway.
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Affiliation(s)
- Zhou Lu Wei
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China. .,Faculty of Basic Medicine, Guilin Medical University, No. 109, Guilin 541004, P. R. China
| | - Wang Juan
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China. .,Key Laboratory of Pharmacognosy, Education Department of Guangxi Zhuang Autonomous Region, 541199, P. R. China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, 541001, P. R. China.,Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.,Faculty of Basic Medicine, Guilin Medical University, No. 109, Guilin 541004, P. R. China
| | - Dou Tong
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China. .,School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China
| | - Li Xiao Juan
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
| | - Liu Yi Sa
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
| | - Huang Fu Meng Jie
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
| | - Guan Xiao
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
| | - Liu Guo Xiang
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
| | - Han Meng Jie
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
| | - Chen Xu
- Department of Pharmacy, Guilin Medical University, Guilin 541199, P. R. China.
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Zhang H, Liu Y, Yao M, Han W, Zhang S. Cathodic Electrochemiluminesence Microscopy for Imaging of Single Carbon Nanotube and Nucleolin at Single Tumor Cell. Anal Chem 2023; 95:570-574. [PMID: 36596251 DOI: 10.1021/acs.analchem.2c04425] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Cathodic electrochemiluminesence (ECL) microscopy based on luminol analog L012 was originally established to implement the imaging of a single nanotube and nucleolin on a single tumor cell. This microscopy utilizes multiwalled carbon nanotubes (MWCNTs) as advanced coreactant accelerators to efficiently convert dissolved oxygen (O2) and H2O2 into reactive oxygen species (ROS) due to excellent electrocatalytic properties. The produced ROS could oxide L012 into an excited state of L012 leading to a bright cathodic ECL illumination, thereby promoting ECL imaging of MWCNTs at a low triggering potential. After being modified with AS1411 aptamers, MWCNTs@AS1411 probes were incubated with tumor cells for specific ECL imaging of nucleolin on the plasma membrane, which permits cathodic ECL microscopy for label-free bioassays without ECL tags. The L012-based cathodic ECL microscopy with a moderate operating potential and label-free characteristics provides a universal approach in single nanomaterial and single-cell imaging and analyses.
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Affiliation(s)
- Huairong Zhang
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi, 276005, China
| | - Yong Liu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China
| | - Mei Yao
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi, 276005, China
| | - Wenxiu Han
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi, 276005, China
| | - Shusheng Zhang
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi, 276005, China
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