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Miranda-Alban J, Sanchez-Luege N, Valbuena FM, Rangel C, Rebay I. The Abelson kinase and the Nedd4 family E3 ligases co-regulate Notch trafficking to limit signaling. J Cell Biol 2025; 224:e202407066. [PMID: 40183942 PMCID: PMC11970431 DOI: 10.1083/jcb.202407066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 01/25/2025] [Accepted: 03/05/2025] [Indexed: 04/05/2025] Open
Abstract
Precise output from the conserved Notch signaling pathway governs a plethora of cellular processes and developmental transitions. Unlike other pathways that use a cytoplasmic relay, the Notch cell surface receptor transduces signaling directly to the nucleus, with endocytic trafficking providing critical regulatory nodes. Here we report that the cytoplasmic tyrosine kinase Abelson (Abl) facilitates Notch internalization into late endosomes/multivesicular bodies (LEs), thereby limiting signaling output in both ligand-dependent and -independent contexts. Abl phosphorylates the PPxY motif within Notch, a molecular target for its degradation via Nedd4 family ubiquitin ligases. We show that Su(dx), a family member, mediates the Abl-directed LE regulation of Notch via the PPxY, while another family member, Nedd4Lo, contributes to Notch internalization into LEs through both PPxY-dependent and -independent mechanisms. Our findings demonstrate how a network of posttranslational modifiers converging at LEs cooperatively modulates Notch signaling to ensure the precision and robustness of its cellular and developmental functions.
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Affiliation(s)
- Julio Miranda-Alban
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, IL, USA
| | - Nicelio Sanchez-Luege
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, IL, USA
| | - Fernando M. Valbuena
- Cell and Molecular Biology Graduate Program, University of Chicago, Chicago, IL, USA
| | - Chyan Rangel
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - Ilaria Rebay
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, IL, USA
- Cell and Molecular Biology Graduate Program, University of Chicago, Chicago, IL, USA
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
- Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, USA
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2
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Alimohammadi M, Kahkesh S, Abbasi A, Hashemi M, Khoshnazar SM, Taheriazam A, Hushmandi K. LncRNAs and IgA nephropathy: underlying molecular pathways and clinical applications. Clin Exp Med 2025; 25:140. [PMID: 40328979 PMCID: PMC12055897 DOI: 10.1007/s10238-025-01660-9] [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: 03/06/2025] [Accepted: 04/01/2025] [Indexed: 05/08/2025]
Abstract
IgA nephropathy (IgAN), also known as Berger's disease, is a prevalent kidney disorder caused by the accumulation of IgA antibodies in the glomerular tissue. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs longer than 200 nucleotides, play crucial roles in regulating various cellular and molecular processes, including translation, chromatin remodeling, and transcriptional efficiency. Research has highlighted the significant impact of lncRNA imbalances on the development and progression of kidney diseases, including IgAN. These molecules influence several key signaling pathways, such as PI3K/AKT/mTOR, PTEN, Notch, JNK, and immune-related pathways, with their dysregulation contributing to IgAN pathogenesis. This review aims to provide a comprehensive analysis of the molecular signaling pathways involving lncRNAs in IgAN, underscoring their potential as biomarkers for screening, diagnosis, and prevention. Furthermore, it explores the therapeutic potential of lncRNAs as precise targets for personalized treatment strategies.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amirhosein Abbasi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Seyedeh Mahdieh Khoshnazar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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3
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Lemmex ACD, Allred J, Ostergard J, Trask J, Bui HN, Anderson MJM, Kopp B, Streeter O, Smiley AT, Babilonia-Díaz NS, Blazar BR, Higgins L, Gordon PM, Muretta JM, Gordon WR. Single-Chain Nanobody Inhibition of Notch and Avidity Enhancement Utilizing the β-Pore-Forming Toxin Aerolysin. ACS Chem Biol 2025; 20:656-669. [PMID: 40079390 DOI: 10.1021/acschembio.4c00803] [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] [Indexed: 03/15/2025]
Abstract
Notch plays critical roles in developmental processes and disease pathogenesis, which have led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling derived from a synthetic phage-display library targeting the Notch negative regulatory region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay with an IC50 of about 5 μM and in a Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19 μM affinity for the Notch NRR. We addressed the low affinity by fusion to a mutant varient of the β-pore-forming toxin aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with efficacy similar to that of other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.
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Affiliation(s)
- Andrew C D Lemmex
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Jeremy Allred
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Jason Ostergard
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Jake Trask
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Hannah N Bui
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Michael J M Anderson
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Benjamin Kopp
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Oakley Streeter
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Adam T Smiley
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | | | - Bruce R Blazar
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - LeeAnn Higgins
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Peter M Gordon
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Joseph M Muretta
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
| | - Wendy R Gordon
- University of Minnesota, Twin Cities, Minneapolis, Minnesota 55409, United States
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4
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Joy N, Deshpande A, Lingamallu SM, Prabantu VM, Naveenkumar CN, Bharathkumar K, Bhat S, Alvarado-Martinez Z, Livraghi-Butrico A, Hagood JS, Boucher RC, Lafkas D, Byrd KM, Narayanan S, Shandil RK, Guha A. Notch signaling stabilizes lengths of motile cilia in multiciliated cells in the lung. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.12.628112. [PMID: 39713474 PMCID: PMC11661201 DOI: 10.1101/2024.12.12.628112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Airway multiciliated cells (MCs) maintain respiratory health by clearing mucus and trapped particles through the beating of motile cilia. While it is known that ciliary lengths decrease along the proximal-distal (P-D) axis of the tracheobronchial tree, how this is regulated is unclear. Here, we demonstrate that canonical Notch signaling in MCs plays a critical role in stabilizing ciliary length. Inhibition of Notch signaling in MCs results in ciliary shortening in the trachea, lengthening in the distal airway, and to region-specific alterations in gene expression. We probe how environmental challenges impact MC homeostasis using germ-free and Mycobacterium tuberculosis ( M. tb ) infection models. While germ-free conditions do not perturb ciliary lengths, M. tb infection leads to lengthening of distal airway cilia, correlating with a downregulation of Notch signaling. These findings reveal that ciliary length and the P-D gradient in the airways are actively regulated, with Notch signaling serving as a stabilizing mechanism.
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5
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Chouly M, Bally-Cuif L. Generating neurons in the embryonic and adult brain: compared principles and mechanisms. C R Biol 2024; 347:199-221. [PMID: 39535540 DOI: 10.5802/crbiol.167] [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: 08/31/2024] [Revised: 10/06/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024]
Abstract
Neurogenesis is a lifelong process, generating neurons in the right amount, time and place and with the correct identity to permit the growth, function, plasticity and repair of the nervous system, notably the brain. Neurogenesis originates from neural progenitor cells (NPs), endowed with the capacity to divide, renew to maintain the progenitor population, or commit to engage in the neurogenesis process. In the adult brain, these progenitors are classically called neural stem cells (NSCs). We review here the commonalities and differences between NPs and NSCs, in their cellular and molecular attributes but also in their potential, regulators and lineage, in the embryonic and adult brains. Our comparison is based on the two most studied model systems, namely the telencephalon of the zebrafish and mouse. We also discuss how the population of embryonic NPs gives rise to adult NSCs, and outstanding questions pertaining to this transition.
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6
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Abdel-Naby DH, El-Sheikh MM, Abd El-Rahman SS, El-Hamoly T. GSK-3β/Notch-1 Activation Promotes Radiation-Induced Renal Damage: The Role of Gallic Acid in Mitigation of Nephrotoxicity. ENVIRONMENTAL TOXICOLOGY 2024; 39:4871-4883. [PMID: 38894622 DOI: 10.1002/tox.24361] [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: 12/17/2023] [Revised: 04/20/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024]
Abstract
Despite the therapeutic advances in treating malignancies, the efficient radiotherapeutic approaches with deprived adverse reactions still represent a potential clinical inquiry. The current study aims to elucidate the role of gallic acid (GA) in modifying the hazardous renal cytotoxicity induced by acute exposure to radiation. The MTT test was used to evaluate the viability of Vero cells exposed to 2 Gy gamma radiation with or without incubation of GA. In an in vivo model, male Wistar rats were divided into four experimental groups (n = 6): Control, Irradiated (IRR, 5 Gy), GA (100 mg/kg, i.p.) + IRR, and Glycogen synthase kinase inhibitor (GSKI, 3 mg/kg, i.p.) + IRR. Based on the MTT toxicity assay, from 0 and up to 5 μM dosages of GA did not demonstrate any cytotoxicity to Vero cells. The optimal GA dose that could protect the cells from radiation was 5 μM. Furthermore, GA exerted a protective effect from gamma radiation on renal tissue as indicated by corrected renal functions, decreased LDH level in serum, and balanced oxidative status, which is indicated by decreased tissue contents of NOx and TBARS with a significant increase of reduced GSH. These outcomes were inferred by the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. The overall molecular impact of radiation in damaging the renal tissue may be explained by modifying the upstream AKT activity and its downstream targets GSK-3β/Notch-1. Here, we concluded that the anticipated adverse reaction in the course of radiation exposure could be protected by daily administration of GA.
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Affiliation(s)
- Doaa H Abdel-Naby
- Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Marwa M El-Sheikh
- Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Sahar S Abd El-Rahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Tarek El-Hamoly
- Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
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7
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Lemmex AC, Allred J, Ostergard J, Trask J, Bui HN, Anderson MJM, Kopp B, Streeter O, Smiley AT, Babilonia-Díaz NS, Blazar BR, Higgins L, Gordon PM, Muretta JM, Gordon WR. Single-chain nanobody inhibition of Notch and avidity enhancement utilizing the β-pore forming toxin Aerolysin. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.22.617501. [PMID: 39484510 PMCID: PMC11526928 DOI: 10.1101/2024.10.22.617501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Notch plays critical roles in developmental processes and disease pathogenesis, which has led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling, derived from a synthetic phage-display library targeting the notch Negative Regulatory Region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay and in Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19uM affinity for Notch. We addressed the low affinity by fusion to a membrane-associating domain derived from the β-Pore forming toxin Aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with similar efficacy to other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody, and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.
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Affiliation(s)
| | | | | | - Jake Trask
- University of Minnesota, Twin Cities. Minneapolis, MN 55409
| | - Hannah N. Bui
- University of Minnesota, Twin Cities. Minneapolis, MN 55409
| | | | - Benjamin Kopp
- University of Minnesota, Twin Cities. Minneapolis, MN 55409
| | | | - Adam T. Smiley
- University of Minnesota, Twin Cities. Minneapolis, MN 55409
| | | | | | - LeAnn Higgins
- University of Minnesota, Twin Cities. Minneapolis, MN 55409
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Perez DH, Antfolk D, Bustos XE, Medina E, Chang S, Ramadan AA, Rodriguez PC, Gonzalez-Perez D, Abate-Daga D, Luca VC. Engineering synthetic agonists for targeted activation of Notch signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.06.606897. [PMID: 39149362 PMCID: PMC11326249 DOI: 10.1101/2024.08.06.606897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Notch signaling regulates cell fate decisions and has context-dependent tumorigenic or tumor suppressor functions. Although there are several classes of Notch inhibitors, the mechanical force requirement for Notch receptor activation has hindered attempts to generate soluble agonists. To address this problem, we engineered synthetic Notch agonist (SNAG) proteins by tethering affinity-matured Notch ligands to antibodies or cytokines that internalize their targets. This bispecific format enables SNAGs to "pull" on mechanosensitive Notch receptors, triggering their activation in the presence of a desired biomarker. We successfully developed SNAGs targeting six independent surface markers, including the tumor antigens PDL1, CD19, and HER2, and the immunostimulatory receptor CD40. SNAGs targeting CD40 increase expansion of central memory γδ T cells from peripheral blood, highlighting their potential to improve the phenotype and yield of low-abundance T cell subsets. These insights have broad implications for the pharmacological activation of mechanoreceptors and will expand our ability to modulate Notch signaling in biotechnology.
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Affiliation(s)
- David H. Perez
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Daniel Antfolk
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Xiomar E. Bustos
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Elliot Medina
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Shiun Chang
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Ahmed A. Ramadan
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | | | | | - Daniel Abate-Daga
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Vincent C. Luca
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33602, USA
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9
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Ran Y, Han S, Gao D, Chen X, Liu C. Interference of FZD2 suppresses proliferation, vasculogenic mimicry and stemness in glioma cells via blocking the Notch/NF‑κB signaling pathway. Exp Ther Med 2024; 28:373. [PMID: 39091630 PMCID: PMC11292164 DOI: 10.3892/etm.2024.12662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 03/22/2024] [Indexed: 08/04/2024] Open
Abstract
Frizzled family protein 2 (FZD2) is widely associated with tumor development and metastasis. The present study aimed to gain an insight into the role and regulatory mechanism of FZD2 in glioma. The expression level of FZD2 in normal astrocyte and glioma cells was determined by reverse transcription-quantitative PCR and western blotting, and cell transfection was conducted for FZD2 expression knockdown. Malignant behaviors including cell proliferation, migration and invasion, vasculogenic mimicry (VM) and cell stemness were determined using Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine (EdU) staining, colony formation, wound healing, Transwell, 3D culturing and sphere formation assays. The expression levels of proteins related to stemness, epithelial-mesenchymal transition (EMT) and Notch/NF-κB signaling were measured by western blotting. Then, the Notch agonist, Jagged-1 (JAG), was adopted for rescue experiments. The results demonstrated that FZD2 was highly expressed in glioma cells. Interference of FZD2 expression suppressed the proliferation of glioma cells, as evidenced by the reduced cell viability and the number of EdU+ cells and colonies. Meanwhile, the reduced sphere formation ability and decreased protein expression of Nanog, Sox2 and Oct4 following FZD2 knockdown confirmed that FZD2 repressed cell stemness in glioma. Additionally, FZD2 knockdown suppressed the migration, invasion, EMT and VM formation capabilities of glioma cells, and also blocked the Notch/NF-κB signaling pathway. Furthermore, activation of Notch by JAG treatment partially reversed the aforementioned FZD2 knockdown-mediated changes in glioma cell malignant behaviors. In conclusion, FZD2 may contribute to glioma progression through activating the Notch/NF-κB signaling pathway, providing a plausible therapeutic target for the treatment of glioma.
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Affiliation(s)
- Yuge Ran
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Shuai Han
- Department of Medicine, Batai Biopharmaceutical Co., Ltd., Beijing 102600, P.R. China
| | - Dongxue Gao
- Proton Therapy Center, Cancer Hospital Chinese Academy of Medical Sciences, Langfang, Hebei 065000, P.R. China
| | - Xiaobo Chen
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Chan Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
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Sanjeevi M, Mohan A, Ramachandran D, Jeyaraman J, Sekar K. CSSP-2.0: A refined consensus method for accurate protein secondary structure prediction. Comput Biol Chem 2024; 112:108158. [PMID: 39053174 DOI: 10.1016/j.compbiolchem.2024.108158] [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: 12/23/2023] [Revised: 06/19/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024]
Abstract
Studying the relationship between sequences and their corresponding three-dimensional structure assists structural biologists in solving the protein-folding problem. Despite several experimental and in-silico approaches, still understanding or decoding the three-dimensional structures from the sequence remains a mystery. In such cases, the accuracy of the structure prediction plays an indispensable role. To address this issue, an updated web server (CSSP-2.0) has been created to improve the accuracy of our previous version of CSSP by deploying the existing algorithms. It uses input as probabilities and predicts the consensus for the secondary structure as a highly accurate three-state Q3 (helix, strand, and coil). This prediction is achieved using six recent top-performing methods: MUFOLD-SS, RaptorX, PSSpred v4, PSIPRED, JPred v4, and Porter 5.0. CSSP-2.0 validation includes datasets involving various protein classes from the PDB, CullPDB, and AlphaFold databases. Our results indicate a significant improvement in the accuracy of the consensus Q3 prediction. Using CSSP-2.0, crystallographers can sort out the stable regular secondary structures from the entire complex structure, which would aid in inferring the functional annotation of hypothetical proteins. The web server is freely available at https://bioserver3.physics.iisc.ac.in/cgi-bin/cssp-2/.
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Affiliation(s)
- Madhumathi Sanjeevi
- Department of Computational and Data Sciences, Indian Institute of Science, Bangalore 560012, India; Structural Biology and Bio-Computing Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi 630004, India
| | - Ajitha Mohan
- Department of Computational and Data Sciences, Indian Institute of Science, Bangalore 560012, India
| | | | - Jeyakanthan Jeyaraman
- Structural Biology and Bio-Computing Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi 630004, India.
| | - Kanagaraj Sekar
- Department of Computational and Data Sciences, Indian Institute of Science, Bangalore 560012, India.
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Lailler C, Didelot A, Garinet S, Berthou H, Sroussi M, de Reyniès A, Dedhar S, Martin-Lannerée S, Fabre E, Le Pimpec-Barthes F, Perrier A, Poindessous V, Mansuet-Lupo A, Djouadi F, Launay JM, Laurent-Puig P, Blons H, Mouillet-Richard S. PrP C controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up. Oncogene 2024; 43:2781-2794. [PMID: 39147880 PMCID: PMC11379626 DOI: 10.1038/s41388-024-03130-0] [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: 05/23/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/17/2024]
Abstract
Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.
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Affiliation(s)
- Claire Lailler
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Audrey Didelot
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Simon Garinet
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Hugo Berthou
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Marine Sroussi
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France
| | - Aurélien de Reyniès
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Shoukat Dedhar
- Genetics Unit, Integrative Oncology, BC Cancer, Vancouver, BC, Canada
| | - Séverine Martin-Lannerée
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Elizabeth Fabre
- AP-HP Department of Thoracic Oncology, Hôpital Européen Georges Pompidou, Paris, France
| | | | - Alexandre Perrier
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Virginie Poindessous
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Audrey Mansuet-Lupo
- AP-HP Department of Pathology, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Fatima Djouadi
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Jean-Marie Launay
- INSERM U942 Lariboisière Hospital, Paris, France
- Pharma Research Department, F. Hoffmann-La-Roche Ltd., Basel, Switzerland
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France
| | - Hélène Blons
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.
- Institut du Cancer Paris CARPEM, AP-HP, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Hôpital Européen Georges Pompidou, Paris, France.
| | - Sophie Mouillet-Richard
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.
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DeCotiis-Mauro J, Han SM, Mello H, Goyeneche C, Marchesini-Tovar G, Jin L, Bellofatto V, Lukac DM. The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner. J Virol 2024; 98:e0078824. [PMID: 38975769 PMCID: PMC11334469 DOI: 10.1128/jvi.00788-24] [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: 05/06/2024] [Accepted: 06/05/2024] [Indexed: 07/09/2024] Open
Abstract
The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi's sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi's sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma-secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene-specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces the production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for the robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA-binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces the expression of specific viral genes yet does not affect the growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta's ability to redistribute RBP-Jk DNA binding to the virus during reactivation.
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Affiliation(s)
- Jennifer DeCotiis-Mauro
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - Sun M. Han
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - Helena Mello
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - Corey Goyeneche
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - Giuseppina Marchesini-Tovar
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - Lianhua Jin
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - Vivian Bellofatto
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
| | - David M. Lukac
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
- School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA
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Hack SJ, Petereit J, Tseng KAS. Temporal Transcriptomic Profiling of the Developing Xenopus laevis Eye. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.20.603187. [PMID: 39091861 PMCID: PMC11291033 DOI: 10.1101/2024.07.20.603187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Retinal progenitor cells (RPCs) are a multipotent and highly proliferative population that give rise to all retinal cell types during organogenesis. Defining their molecular signature is a key step towards identifying suitable approaches to treat visual impairments. Here, we performed RNA-sequencing of whole eyes from Xenopus at three embryonic stages and used differential expression analysis to define the transcriptomic profiles of optic tissues containing proliferating and differentiating RPCs during retinogenesis. Gene Ontology and KEGG pathway analyses showed that genes associated with developmental pathways (including Wnt and Hedgehog signaling) were upregulated during the period of active RPC proliferation in early retinal development (Nieuwkoop Faber st. 24 and 27). Developing eyes had dynamic expression profiles and shifted to enrichment for metabolic processes and phototransduction during RPC progeny specification and differentiation (st. 35). Furthermore, conserved adult eye regeneration genes were also expressed during early retinal development including sox2, pax6, nrl, and Notch signaling components. The eye transcriptomic profiles presented here span RPC proliferation to retinogenesis and included regrowth-competent stages. Thus, our dataset provides a rich resource to uncover molecular regulators of RPC activity and will allow future studies to address regulators of RPC proliferation during eye repair and regrowth.
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Affiliation(s)
- Samantha J. Hack
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA
| | - Juli Petereit
- Nevada Bioinformatics Center, University of Nevada, Reno
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14
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Ramsey KM, Barrick D. Unraveling paralog-specific Notch signaling through thermodynamics of ternary complex formation and transcriptional activation of chimeric receptors. Protein Sci 2024; 33:e4947. [PMID: 38511488 PMCID: PMC10962485 DOI: 10.1002/pro.4947] [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: 10/25/2023] [Revised: 02/07/2024] [Accepted: 02/11/2024] [Indexed: 03/22/2024]
Abstract
Notch signaling in humans is mediated by four paralogous receptors that share conserved architectures and possess overlapping, yet non-redundant functions. The receptors share a canonical activation pathway wherein upon extracellular ligand binding, the Notch intracellular domain (NICD) is cleaved from the membrane and translocates to the nucleus where its N-terminal RBP-j-associated molecule (RAM) region and ankyrin repeat (ANK) domain bind transcription factor CSL and recruit co-activator Mastermind-like-1 (MAML1) to activate transcription. However, different paralogs can lead to distinct outcomes. To better understand paralog-specific differences in Notch signaling, we performed a thermodynamic analysis of the Notch transcriptional activation complexes for all four Notch paralogs using isothermal titration calorimetry. Using chimeric constructs, we find that the RAM region is the primary determinant of stability of binary RAMANK:CSL complexes, and that the ANK regions are largely the determinants of MAML1 binding to pre-formed RAMANK:CSL complexes. Free energies of these binding reactions (ΔGRA and ΔGMAML) vary among the four Notch paralogs, although variations for Notch2, 3, and 4 offset in the free energy of the ternary complex (ΔGTC, where ΔGTC = ΔGRA + ΔGMAML). To probe how these affinity differences affect Notch signaling, we performed transcriptional activation assays with the paralogous and chimeric NICDs, and analyzed the results with an independent multiplicative model that quantifies contributions of the paralogous RAM, ANK, and C-terminal regions (CTR) to activation. This analysis shows that transcription activation correlates with ΔGTC, but that activation is further modified by CTR identity in a paralog-specific way.
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Affiliation(s)
- Kristen M. Ramsey
- T.C. Jenkins Department of BiophysicsJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Doug Barrick
- T.C. Jenkins Department of BiophysicsJohns Hopkins UniversityBaltimoreMarylandUSA
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15
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Kumari L, Mishra L, Sharma Y, Chahar K, Kumar M, Patel P, Gupta GD, Kurmi BD. NOTCH Signaling Pathway: Occurrence, Mechanism, and NOTCH-Directed Therapy for the Management of Cancer. Cancer Biother Radiopharm 2024; 39:19-34. [PMID: 37797218 DOI: 10.1089/cbr.2023.0023] [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] [Indexed: 10/07/2023] Open
Abstract
It is now well understood that many signaling pathways are vital in carrying out and controlling essential pro-survival and pro-growth cellular functions. The NOTCH signaling pathway, a highly conserved evolutionary signaling pathway, has been thoroughly studied since the discovery of NOTCH phenotypes about 100 years ago in Drosophila melanogaster. Abnormal NOTCH signaling has been linked to the pathophysiology of several diseases, notably cancer. In tumorigenesis, NOTCH plays the role of a "double-edged sword," that is, it may act as an oncogene or as a tumor suppressor gene depending on the nature of the context. However, its involvement in several cancers and inhibition of the same provides targeted therapy for the management of cancer. The use of gamma (γ)-secretase inhibitors and monoclonal antibodies for cancer treatment involved NOTCH receptors inhibition, leading to the possibility of a targeted approach for cancer treatment. Likewise, several natural compounds, including curcumin, resveratrol, diallyl sulfide, and genistein, also play a dynamic role in the management of cancer by inhibition of NOTCH receptors. This review outlines the functions and structure of NOTCH receptors and their associated ligands with the mechanism of the signaling pathway. In addition, it also emphasizes the role of NOTCH-targeted nanomedicine in various cancer treatment strategies.
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Affiliation(s)
- Lakshmi Kumari
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | | | - Yash Sharma
- Department of Pharmaceutical Quality Assurance, ISF College Pharmacy, Moga, India
| | - Kanak Chahar
- Department of Pharmaceutical Quality Assurance, ISF College Pharmacy, Moga, India
| | - Mritunjay Kumar
- Department of Pharmaceutical Quality Assurance, ISF College Pharmacy, Moga, India
| | - Preeti Patel
- Department of Pharmaceutical Chemistry, ISF College Pharmacy, Moga, India
| | | | - Balak Das Kurmi
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
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16
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Nikoloudaki G, Basdeki EI, Kerezoudis NP, Tosios KI. Notch-1/2 receptors and Jagged-1 ligand, but not HERP-1 transcription factor, are immunohistochemically expressed in the epithelial lining of periapical cysts. J Clin Exp Dent 2024; 16:e25-e31. [PMID: 38314334 PMCID: PMC10837808 DOI: 10.4317/jced.61008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/14/2023] [Indexed: 02/06/2024] Open
Abstract
Background To further understand the involvement of Notch pathway signaling in the pathogenesis of periapical cyst the immunohistochemical expression of Notch-1 and Notch-2 receptors, Jagged-1 ligand, and HERP-1 transcription factor in the lining epithelium of periapical cysts was investigated. Material and Methods Thirty human periapical cysts were immunohistochemically stained with antibodies against Notch-1, Notch-2, Jagged-1, and HERP-1. Epithelial expression of each antibody was correlated with the presence of inflammation in the connective tissue of the cystic wall. Results Notch-1 was identified in the basal and suprabasal epithelial cells of 30/30, Notch-2 in 19/24, and Jagged-1 in 27/30 cysts. HERP-1 was detected in scattered subepithelial inflammatory cells, but not in the lining epithelium of cysts. There was no significant correlation between the immunohistochemical expression of each antibody and the presence of inflammation in the connective tissue of the cystic wall. Conclusions This immunohistochemical study showed expression of Notch-1/2 and Jagged-1 in periapical cysts that combined with the expression of HES1/5 found in a previous report, are indicative of the activation of Notch an endocrine-paracrine mechanism. Further research on the activity of Notch and other pathways in periapical cysts may contribute both to elucidate their pathogenesis and select molecular targets for future novel treatments. Key words:Odontogenic cyst, radicular cyst, etiology, epithelial cells, Notch, Jagged, HERP.
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Affiliation(s)
- Georgia Nikoloudaki
- Assistant Professor, Schulich Medicine & Dentistry, Western University, London, Ontario, Canada
| | | | - Nikolaos P Kerezoudis
- Professor and Chairman, Department of Endodontics, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos I Tosios
- Associate Professor, Department of Oral Medicine, Pathology & Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece
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17
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Mora P, Chapouly C. Astrogliosis in multiple sclerosis and neuro-inflammation: what role for the notch pathway? Front Immunol 2023; 14:1254586. [PMID: 37936690 PMCID: PMC10627009 DOI: 10.3389/fimmu.2023.1254586] [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: 07/07/2023] [Accepted: 10/09/2023] [Indexed: 11/09/2023] Open
Abstract
Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system leading to neurodegeneration. It affects 2.3 million people worldwide, generally younger than 50. There is no known cure for the disease, and current treatment options - mainly immunotherapies to limit disease progression - are few and associated with serious side effects. In multiple sclerosis, disruption of the blood-brain barrier is an early event in the pathogenesis of lesions, predisposing to edema, excito-toxicity and inflammatory infiltration into the central nervous system. Recently, the vision of the blood brain barrier structure and integrity has changed and include contributions from all components of the neurovascular unit, among which astrocytes. During neuro-inflammation, astrocytes become reactive. They undergo morphological and molecular changes named "astrogliosis" driving the conversion from acute inflammatory injury to a chronic neurodegenerative state. Astrogliosis mechanisms are minimally explored despite their significance in regulating the autoimmune response during multiple sclerosis. Therefore, in this review, we take stock of the state of knowledge regarding astrogliosis in neuro-inflammation and highlight the central role of NOTCH signaling in the process of astrocyte reactivity. Indeed, a very detailed nomenclature published in nature neurosciences in 2021, listing all the reactive astrocyte markers fully identified in the literature, doesn't cover the NOTCH signaling. Hence, we discuss evidence supporting NOTCH1 receptor as a central regulator of astrogliosis in the pathophysiology of neuro-inflammation, notably multiple sclerosis, in human and experimental models.
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Affiliation(s)
- Pierre Mora
- Université de Bordeaux, Institut national de la santé et de la recherche médicale (INSERM), Biology of Cardiovascular Diseases, Pessac, France
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18
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Kapturska KM, Pawlak A. New molecular targets in canine hemangiosarcoma-Comparative review and future of the precision medicine. Vet Comp Oncol 2023; 21:357-377. [PMID: 37308243 DOI: 10.1111/vco.12917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 05/10/2023] [Accepted: 05/30/2023] [Indexed: 06/14/2023]
Abstract
Human angiosarcoma and canine hemangiosarcoma reveal similarities not only in their aggressive clinical behaviour, but especially in molecular landscape and genetic alterations involved in tumorigenesis and metastasis formation. Currently, no satisfying treatment that allows for achieving long overall survival or even prolonged time to progression does not exist. Due to the progress that has been made in targeted therapies and precision medicine the basis for a new treatment design is to uncover mutations and their functions as possible targets to provide tailored drugs for individual cases. Whole exome or genome sequencing studies and immunohistochemistry brought in the last few years important discoveries and identified the most common mutations with probably crucial role in this tumour development. Also, despite a lack of mutation in some of the culprit genes, the cancerogenesis cause may be buried in main cellular pathways connected with proteins encoded by those genes and involving, for example, pathological angiogenesis. The aim of this review is to highlight the most promising molecular targets for precision oncology treatment from the veterinary perspective aided by the principles of comparative science. Some of the drugs are only undergoing laboratory in vitro studies and others entered the clinic in the management of other cancer types in humans, but those used in dogs with promising responses have been mentioned as priorities.
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Affiliation(s)
- Karolina Małgorzata Kapturska
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
- Veterinary Clinic NEOVET s.c. Hildebrand, Jelonek, Michalek-Salt, Wroclaw, Poland
| | - Aleksandra Pawlak
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
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19
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Feitelson MA, Arzumanyan A, Medhat A, Spector I. Short-chain fatty acids in cancer pathogenesis. Cancer Metastasis Rev 2023; 42:677-698. [PMID: 37432606 PMCID: PMC10584782 DOI: 10.1007/s10555-023-10117-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/05/2023] [Indexed: 07/12/2023]
Abstract
Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of "health," is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a "leaky gut," permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA.
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA
| | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran, 1975933411, Iran
| | - Ira Spector
- SFA Therapeutics, Jenkintown, PA, 19046, USA
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Martinez Lyons A, Boulter L. NOTCH signalling - a core regulator of bile duct disease? Dis Model Mech 2023; 16:dmm050231. [PMID: 37605966 PMCID: PMC10461466 DOI: 10.1242/dmm.050231] [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] [Indexed: 08/23/2023] Open
Abstract
The Notch signalling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.
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Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
- CRUK Scottish Centre, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
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21
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Zhang Y, Wang T, Wu S, Tang L, Wang J, Yang J, Yao S, Zhang Y. Notch signaling pathway: a new target for neuropathic pain therapy. J Headache Pain 2023; 24:87. [PMID: 37454050 PMCID: PMC10349482 DOI: 10.1186/s10194-023-01616-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
The Notch gene, a highly evolutionarily conserved gene, was discovered approximately 110 years ago and has been found to play a crucial role in the development of multicellular organisms. Notch receptors and their ligands are single-pass transmembrane proteins that typically require cellular interactions and proteolytic processing to facilitate signal transduction. Recently, mounting evidence has shown that aberrant activation of the Notch is correlated with neuropathic pain. The activation of the Notch signaling pathway can cause the activation of neuroglia and the release of pro-inflammatory factors, a key mechanism in the development of neuropathic pain. Moreover, the Notch signaling pathway may contribute to the persistence of neuropathic pain by enhancing synaptic transmission and calcium inward flow. This paper reviews the structure and activation of the Notch signaling pathway, as well as its potential mechanisms of action, to provide novel insights for future treatments of neuropathic pain.
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Affiliation(s)
- Yan Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Tingting Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Sanlan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Li Tang
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jia Wang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Health and Rehabilitation Science, Research Center for Brain-Inspired Intelligence, School of Life Science and Technology, Xi'an Jiaotong University, The Key Laboratory of Neuro-Informatics & Rehabilitation En-Gineering of Ministry of Civil Affairs, Xi'an, Shaanxi, P. R. China
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan, 430022, Hubei, China
| | - Jinghan Yang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
| | - Yan Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
- Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.
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22
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Mitsiadis TA, Pagella P, Capellini TD, Smith MM. The Notch-mediated circuitry in the evolution and generation of new cell lineages: the tooth model. Cell Mol Life Sci 2023; 80:182. [PMID: 37330998 DOI: 10.1007/s00018-023-04831-7] [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: 03/14/2023] [Revised: 05/19/2023] [Accepted: 06/09/2023] [Indexed: 06/20/2023]
Abstract
The Notch pathway is an ancient, evolutionary conserved intercellular signaling mechanism that is involved in cell fate specification and proper embryonic development. The Jagged2 gene, which encodes a ligand for the Notch family of receptors, is expressed from the earliest stages of odontogenesis in epithelial cells that will later generate the enamel-producing ameloblasts. Homozygous Jagged2 mutant mice exhibit abnormal tooth morphology and impaired enamel deposition. Enamel composition and structure in mammals are tightly linked to the enamel organ that represents an evolutionary unit formed by distinct dental epithelial cell types. The physical cooperativity between Notch ligands and receptors suggests that Jagged2 deletion could alter the expression profile of Notch receptors, thus modifying the whole Notch signaling cascade in cells within the enamel organ. Indeed, both Notch1 and Notch2 expression are severely disturbed in the enamel organ of Jagged2 mutant teeth. It appears that the deregulation of the Notch signaling cascade reverts the evolutionary path generating dental structures more reminiscent of the enameloid of fishes rather than of mammalian enamel. Loss of interactions between Notch and Jagged proteins may initiate the suppression of complementary dental epithelial cell fates acquired during evolution. We propose that the increased number of Notch homologues in metazoa enabled incipient sister cell types to form and maintain distinctive cell fates within organs and tissues along evolution.
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Affiliation(s)
- Thimios A Mitsiadis
- Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Plattenstrasse 11, 8032, Zurich, Switzerland.
| | - Pierfrancesco Pagella
- Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Plattenstrasse 11, 8032, Zurich, Switzerland
- Wallenberg Center for Molecular Medicine (WCMM) and Department of Biomedical and Clinical Sciences, Linköpings Universitet, 581 85, Linköping, Sweden
| | - Terence D Capellini
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, 02138, USA
| | - Moya Meredith Smith
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, King's College London, London, UK
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23
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Lu C, Zhang J, Wang B, Gao Q, Ma K, Pei S, Li J, Cui S. Casein kinase 1α is required to maintain murine hypothalamic pro-opiomelanocortin expression. iScience 2023; 26:106670. [PMID: 37168577 PMCID: PMC10165255 DOI: 10.1016/j.isci.2023.106670] [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: 12/13/2022] [Revised: 02/08/2023] [Accepted: 04/11/2023] [Indexed: 05/13/2023] Open
Abstract
Hypothalamic pro-opiomelanocortin (POMC) neuron development is considered to play an essential role in the development of obesity. However, the underlying mechanisms remain unclear. Casein kinase 1α (CK1α) was expressed in the embryonic mouse hypothalamus at high levels and colocalized with POMC neurons. CK1α deletion in POMC neurons caused weight gain, metabolic defects, and increased food intake. The number of POMC-expressing cells was considerably decreased in Csnk1a1fl/fl;POMCcre (PKO) mice from embryonic day 15.5 to postnatal day 60, while apoptosis of POMC neurons was not affected. Furthermore, unchanged POMC progenitor cells and a decreased POMC phenotype established CK1α function in hypothalamic POMC neuron development. CK1α deletion led to elevated Notch intracellular domain (NICD) protein expression, and NICD inhibition rescued the PKO mouse phenotype. In summary, CK1α is involved in hypothalamic POMC expression via NICD-POMC signaling, deepening our understanding of POMC neuron development and control of systemic metabolic functions.
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Affiliation(s)
- Chenyang Lu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
| | - Jinglin Zhang
- Institute of Reproduction and Metabolism, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
| | - Bingjie Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
| | - Qiao Gao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
| | - Kezhe Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
| | - Shaona Pei
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
| | - Juxue Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Sheng Cui
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
- Institute of Reproduction and Metabolism, Yangzhou University, Yangzhou, Jiangsu 225009, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People’s Republic of China
- Corresponding author
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24
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Xie L, Yan J. γ-tocotrienol regulates gastric cancer by targeting notch signaling pathway. Hereditas 2023; 160:15. [PMID: 37055846 PMCID: PMC10100483 DOI: 10.1186/s41065-023-00277-w] [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: 02/27/2023] [Accepted: 03/28/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Gastric cancer is a common cause of death from cancer and an important global health care issue. Consequently, there is an urgent need to find new drugs and therapeutic targets for the treatment of gastric cancer. Recent studies have shown that tocotrienols (T3) have significant anticancer ability in cancer cell lines. Our previous study found that γ-tocotrienol (γ-T3) induced apoptosis in gastric cancer cells. We further explored the possible mechanisms of γ-T3 therapy for gastric cancer. METHODS In this study, we treated gastric cancer cells with γ-T3, collect and deposit the cells. γ-T3-treated gastric cancer cells group and untreated group were subjected to RNA-seq assay, and analysis of sequencing results. RESULTS Consistent with our previous findings, the results suggest that γ-T3 can inhibit mitochondrial complexes and oxidative phosphorylation. Analysis reveals that γ-T3 has altered mRNA and ncRNA in gastric cancer cells. Significantly altered signaling pathways after γ-T3 treatment were enriched for human papillomavirus infection (HPV) pathway and notch signaling pathway. The same significantly down-regulated genes notch1 and notch2 were present in both pathways in γ-T3-treated gastric cancer cells compared to controls. CONCLUSIONS It is indicated that γ-T3 may cure gastric cancer by inhibiting the notch signaling pathway. To provide a new and powerful basis for the clinical treatment of gastric cancer.
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Affiliation(s)
- Ling Xie
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Juan Yan
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China.
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25
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Feng J, Wu Y. Endothelial-to-Mesenchymal Transition: Potential Target of Doxorubicin-Induced Cardiotoxicity. Am J Cardiovasc Drugs 2023; 23:231-246. [PMID: 36841924 DOI: 10.1007/s40256-023-00573-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/02/2023] [Indexed: 02/27/2023]
Abstract
The use of chemotherapeutic agents is becoming more frequent as the proportion of new oncology patients increases worldwide, with prolonged survival after treatment. As one of the most popular chemotherapy drugs, doxorubicin plays a substantial role in the treatment of tumors. Unfortunately, the use of doxorubicin is associated with several adverse effects, particularly severe cardiotoxicity that can be life-threatening, which greatly limits its clinical use. For decades, scientists have tried to explore many cardioprotective agents and therapeutic approaches, but their efficacy remains controversial, and some drugs have even brought about significant adverse effects. The concrete molecular mechanism of doxorubicin-induced cardiotoxicity is still to be unraveled, yet endothelial damage is gradually being identified as an important mechanism triggering the development and progression of doxorubicin-induced cardiotoxicity. Endothelial-to-mesenchymal transition (EndMT), a fundamental process regulating morphogenesis in multicellular organisms, is recognized to be associated with endothelial damage repair and acts as an important factor in the progression of cardiovascular diseases, tumors, and rheumatic immune diseases. Mounting evidence suggests that endothelial-mesenchymal transition may play a non-negligible role in doxorubicin-induced cardiotoxicity. In this paper, we reviewed the molecular mechanisms and signaling pathways of EndMT and outlined the molecular mechanisms of doxorubicin-induced cardiotoxicity and the current therapeutic advances. Furthermore, we summarized the basic principles of doxorubicin-induced endothelial-mesenchymal transition that lead to endothelial dysfunction and cardiotoxicity, aiming to provide suggestions or new ideas for the prevention and treatment of doxorubicin-induced endothelial and cardiac injury.
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Affiliation(s)
- Jie Feng
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yanqing Wu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
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26
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Hasan SS, Fischer A. Notch Signaling in the Vasculature: Angiogenesis and Angiocrine Functions. Cold Spring Harb Perspect Med 2023; 13:a041166. [PMID: 35667708 PMCID: PMC9899647 DOI: 10.1101/cshperspect.a041166] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Formation of a functional blood vessel network is a complex process tightly controlled by pro- and antiangiogenic signals released within the local microenvironment or delivered through the bloodstream. Endothelial cells precisely integrate such temporal and spatial changes in extracellular signals and generate an orchestrated response by modulating signaling transduction, gene expression, and metabolism. A key regulator in vessel formation is Notch signaling, which controls endothelial cell specification, proliferation, migration, adhesion, and arteriovenous differentiation. This review summarizes the molecular biology of endothelial Notch signaling and how it controls angiogenesis and maintenance of the established, quiescent vasculature. In addition, recent progress in the understanding of Notch signaling in endothelial cells for controlling organ homeostasis by transcriptional regulation of angiocrine factors and its relevance to disease will be discussed.
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Affiliation(s)
- Sana S Hasan
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Andreas Fischer
- Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Institute for Clinical Chemistry, University Medical Center Göttingen, 37075 Göttingen, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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27
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Zhang C, Xue P, Zhang H, Tan C, Zhao S, Li X, Sun L, Zheng H, Wang J, Zhang B, Lang W. Gut brain interaction theory reveals gut microbiota mediated neurogenesis and traditional Chinese medicine research strategies. Front Cell Infect Microbiol 2022; 12:1072341. [PMID: 36569198 PMCID: PMC9772886 DOI: 10.3389/fcimb.2022.1072341] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/07/2022] [Indexed: 12/13/2022] Open
Abstract
Adult neurogenesis is the process of differentiation of neural stem cells (NSCs) into neurons and glial cells in certain areas of the adult brain. Defects in neurogenesis can lead to neurodegenerative diseases, mental disorders, and other maladies. This process is directionally regulated by transcription factors, the Wnt and Notch pathway, the extracellular matrix, and various growth factors. External factors like stress, physical exercise, diet, medications, etc., affect neurogenesis and the gut microbiota. The gut microbiota may affect NSCs through vagal, immune and chemical pathways, and other pathways. Traditional Chinese medicine (TCM) has been proven to affect NSCs proliferation and differentiation and can regulate the abundance and metabolites produced by intestinal microorganisms. However, the underlying mechanisms by which these factors regulate neurogenesis through the gut microbiota are not fully understood. In this review, we describe the recent evidence on the role of the gut microbiota in neurogenesis. Moreover, we hypothesize on the characteristics of the microbiota-gut-brain axis based on bacterial phyla, including microbiota's metabolites, and neuronal and immune pathways while providing an outlook on TCM's potential effects on adult neurogenesis by regulating gut microbiota.
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Affiliation(s)
- Chenxi Zhang
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Peng Xue
- Medical School of Nantong University, Nantong University, Nantong, China
| | - Haiyan Zhang
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Chenxi Tan
- Department of Infection Control, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Shiyao Zhao
- Department of Nuclear Medicine, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Xudong Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lihui Sun
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Huihui Zheng
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Jun Wang
- The Academic Affairs Office, Qiqihar Medical University, Qiqihar, China
| | - Baoling Zhang
- Department of Operating Room, Qiqihar First Hospital, Qiqihar, China
| | - Weiya Lang
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China,*Correspondence: Weiya Lang,
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28
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Gao L, Lu J, Li J, Hu Y, Lu Y, Du W, Hu S. Lineage switch in a pediatric patient with KMT2A-MLLT3 from acute megakaryoblastic leukemia to T cell acute lymphoblastic leukemia at the fourth relapse after allo-HSCT: with literature review. Int J Hematol 2022; 117:781-785. [PMID: 36472792 DOI: 10.1007/s12185-022-03504-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022]
Abstract
We present a patient with acute megakaryoblastic leukemia (AMKL) harboring KMT2A-MLLT3 that converted to T cell acute lymphoblastic leukemia (T-ALL) at her fourth relapse. A 4-year-old girl developed AMKL with multiple swollen lymph nodes. She exhibited several recurrences in the bone marrow and died of septic shock after her fourth relapse. Bone marrow cells at the initial diagnosis and at all four relapses had the same KMT2A-MLLT3 fusion transcript. She also developed a somatic mutation (c.7177C > T p.Q2393X) of NOTCH1 at the fourth relapse. This sequential phenotypic and cytogenetic study may yield valuable insights into the mechanism of AMKL to T-ALL lineage switch and possible implications for treatment selection.
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Affiliation(s)
- Li Gao
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Jun Lu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Jie Li
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Yixin Hu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Ye Lu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Weiwei Du
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
| | - Shaoyan Hu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China.
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29
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Stanley P, Tanwar A. Regulation of myeloid and lymphoid cell development by O-glycans on Notch. Front Mol Biosci 2022; 9:979724. [PMID: 36406268 PMCID: PMC9672378 DOI: 10.3389/fmolb.2022.979724] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 10/13/2022] [Indexed: 10/06/2023] Open
Abstract
Notch signaling via NOTCH1 stimulated by Delta-like ligand 4 (DLL4) is required for the development of T cells in thymus, and NOTCH2 stimulated by Notch ligand DLL1 is required for the development of marginal zone (MZ) B cells in spleen. Notch signaling also regulates myeloid cell production in bone marrow and is an essential contributor to the generation of early hematopoietic stem cells (HSC). The differentiation program in each of these cellular contexts is optimized by the regulation of Notch signaling strength by O-glycans attached to epidermal growth factor-like (EGF) repeats in the extracellular domain of Notch receptors. There are three major types of O-glycan on NOTCH1 and NOTCH2 - O-fucose, O-glucose and O-GlcNAc. The initiating sugar of each O-glycan is added in the endoplasmic reticulum (ER) by glycosyltransferases POFUT1 (fucose), POGLUT1/2/3 (glucose) or EOGT (GlcNAc), respectively. Additional sugars are added in the Golgi compartment during passage through the secretory pathway to the plasma membrane. Of particular significance for Notch signaling is the addition of GlcNAc to O-fucose on an EGF repeat by the Fringe GlcNAc-transferases LFNG, MFNG or RFNG. Canonical Notch ligands (DLL1, DLL4, JAG1, JAG2) expressed in stromal cells bind to the extracellular domain of Notch receptors expressed in hematopoietic stem cells and myeloid and lymphoid progenitors to activate Notch signaling. Ligand-receptor binding is differentially regulated by the O-glycans on Notch. This review will summarize our understanding of the regulation of Notch signaling in myeloid and lymphoid cell development by specific O-glycans in mice with dysregulated expression of a particular glycosyltransferase and discuss how this may impact immune system development and malignancy in general, and in individuals with a congenital defect in the synthesis of the O-glycans attached to EGF repeats.
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Affiliation(s)
- Pamela Stanley
- Department of Cell Biology, Albert Einstein College Medicine, New York, NY, United States
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30
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Fechner J, Ketelhut M, Maier D, Preiss A, Nagel AC. The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation. Int J Mol Sci 2022; 23:ijms232012336. [PMID: 36293193 PMCID: PMC9604145 DOI: 10.3390/ijms232012336] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022] Open
Abstract
The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity. Hence, dosage of Notch components is crucial to regulation. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes. CSL proteins are extremely similar amongst species regarding sequence and structure. We noticed that the fly homologue suppressor of hairless (Su(H)) is stabilised in transcription complexes. Using specific transgenic fly lines and HeLa RBPJKO cells we provide evidence that Su(H) is subjected to proteasomal degradation with a half-life of about two hours if not protected by binding to co-repressor hairless or co-activator Notch. Moreover, Su(H) stability is controlled by MAPK-dependent phosphorylation, matching earlier data for RBPJ in human cells. The homologous murine and human RBPJ proteins, however, are largely resistant to degradation in our system. Mutating presumptive protein contact sites, however, sensitised RBPJ for proteolysis. Overall, our data highlight the similarities in the regulation of CSL protein stability across species and imply that turnover of CSL proteins may be a conserved means of regulating Notch signalling output directly at the level of transcription.
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31
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Fan J, Lin B, Fan M, Niu T, Gao F, Tan B, Du X. Research progress on the mechanism of radiation enteritis. Front Oncol 2022; 12:888962. [PMID: 36132154 PMCID: PMC9483210 DOI: 10.3389/fonc.2022.888962] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Radiation enteritis (Re) is one of the most common complications of radiation therapy for abdominal tumors. The efficacy of cancer treatment by radiation is often limited by the side effects of Re. Re can be acute or chronic. Treatment of acute Re is essentially symptomatic. However, chronic Re usually requires surgical procedures. The underlying mechanisms of Re are complex and have not yet been elucidated. The purpose of this review is to provide an overview of the pathogenesis of Re. We reviewed the role of intestinal epithelial cells, intestinal stem cells (ISCs), vascular endothelial cells (ECs), intestinal microflora, and other mediators of Re, noting that a better understanding of the pathogenesis of Re may lead to better treatment modalities.
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Affiliation(s)
- Jinjia Fan
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Binwei Lin
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
| | - Mi Fan
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Tintin Niu
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Feng Gao
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
| | - Bangxian Tan
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Xiaobo Du
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
- *Correspondence: Xiaobo Du,
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32
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Mourkioti I, Angelopoulou A, Belogiannis K, Lagopati N, Potamianos S, Kyrodimos E, Gorgoulis V, Papaspyropoulos A. Interplay of Developmental Hippo-Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer. Cells 2022; 11:cells11152449. [PMID: 35954292 PMCID: PMC9367915 DOI: 10.3390/cells11152449] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related 'hubs' such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR-Hippo-Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.
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Affiliation(s)
- Ioanna Mourkioti
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece
| | - Andriani Angelopoulou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece
| | - Konstantinos Belogiannis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece
| | - Nefeli Lagopati
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece
- Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece
| | - Spyridon Potamianos
- First ENT Department, Hippocration Hospital, University of Athens, 11527 Athens, Greece
| | - Efthymios Kyrodimos
- First ENT Department, Hippocration Hospital, University of Athens, 11527 Athens, Greece
| | - Vassilis Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece
- Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece
- Clinical Molecular Pathology, Medical School, University of Dundee, Dundee DD1 9SY, UK
- Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M20 4GJ, UK
- Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Faculty of Health and Medical Sciences, University of Surrey, Surrey GU2 7YH, UK
- Correspondence: (V.G.); (A.P.); Tel.: +30-210-7462352 (V.G.); +30-210-7462174 (A.P.)
| | - Angelos Papaspyropoulos
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece
- Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece
- Correspondence: (V.G.); (A.P.); Tel.: +30-210-7462352 (V.G.); +30-210-7462174 (A.P.)
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33
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Pani AM, Gibney TV, Medwig-Kinney TN, Matus DQ, Goldstein B. A new toolkit to visualize and perturb endogenous LIN-12/Notch signaling in C. elegans. MICROPUBLICATION BIOLOGY 2022; 2022:10.17912/micropub.biology.000603. [PMID: 35966394 PMCID: PMC9372766 DOI: 10.17912/micropub.biology.000603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/12/2022] [Accepted: 07/24/2022] [Indexed: 11/05/2022]
Abstract
Notch signaling mediates cell-cell interactions during development and homeostasis. Methods for visualizing and manipulating Notch activity in vivo are essential to elucidate how the Notch pathway functions. Here, we provide new tools for use in C. elegans to visualize and perturb Notch signaling in vivo using endogenously tagged alleles of the Notch receptor lin-12 . Tagging the endogenous LIN-12 intracellular domain with the fluorescent protein mNeonGreen (mNG) allowed for visualization of both its membrane-localized state and translocation of the Notch intracellular domain into the nucleus upon ligand activation. LIN-12::mNG localized to the nucleus in cells where and when Notch signaling is known to be active and provided a real-time readout of Notch activity in vivo that complements existing biosensors and transcriptional reporters. We also report an allele of endogenous lin-12 that we tagged with both mNG and an auxin-inducible degron, to facilitate conditional LIN-12 protein degradation. This toolkit provides novel reagents for the C. elegans research community to investigate mechanisms of Notch signaling and its functions in vivo .
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Affiliation(s)
- Ariel M Pani
- Department of Biology, University of Virginia, Charlottesville, VA, USA
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Theresa V Gibney
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | | | - David Q Matus
- Department of Biochemistry & Cell Biology, Stony Brook University, Stony Brook, NY, USA
- D.Q.M. is a paid consultant of Arcadia Science
| | - Bob Goldstein
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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34
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Pulido-Escribano V, Torrecillas-Baena B, Camacho-Cardenosa M, Dorado G, Gálvez-Moreno MÁ, Casado-Díaz A. Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles. World J Stem Cells 2022; 14:453-472. [PMID: 36157530 PMCID: PMC9350626 DOI: 10.4252/wjsc.v14.i7.453] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/02/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
The use of mesenchymal stem-cells (MSC) in cell therapy has received considerable attention because of their properties. These properties include high expansion and differentiation in vitro, low immunogenicity, and modulation of biological processes, such as inflammation, angiogenesis and hematopoiesis. Curiously, the regenerative effect of MSC is partly due to their paracrine activity. This has prompted numerous studies, to investigate the therapeutic potential of their secretome in general, and specifically their extracellular vesicles (EV). The latter contain proteins, lipids, nucleic acids, and other metabolites, which can cause physiological changes when released into recipient cells. Interestingly, contents of EV can be modulated by preconditioning MSC under different culture conditions. Among them, exposure to hypoxia stands out; these cells respond by activating hypoxia-inducible factor (HIF) at low O2 concentrations. HIF has direct and indirect pleiotropic effects, modulating expression of hundreds of genes involved in processes such as inflammation, migration, proliferation, differentiation, angiogenesis, metabolism, and cell apoptosis. Expression of these genes is reflected in the contents of secreted EV. Interestingly, numerous studies show that MSC-derived EV conditioned under hypoxia have a higher regenerative capacity than those obtained under normoxia. In this review, we show the implications of hypoxia responses in relation to tissue regeneration. In addition, hypoxia preconditioning of MSC is being evaluated as a very attractive strategy for isolation of EV, with a high potential for clinical use in regenerative medicine that can be applied to different pathologies.
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Affiliation(s)
- Victoria Pulido-Escribano
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
| | - Bárbara Torrecillas-Baena
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
| | - Marta Camacho-Cardenosa
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, CIBERFES, Córdoba 14071, Spain
| | - María Ángeles Gálvez-Moreno
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
| | - Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
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Lee MY. Embryonic Programs in Cancer and Metastasis—Insights From the Mammary Gland. Front Cell Dev Biol 2022; 10:938625. [PMID: 35846378 PMCID: PMC9277484 DOI: 10.3389/fcell.2022.938625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/07/2022] [Indexed: 11/24/2022] Open
Abstract
Cancer is characterized as a reversion of a differentiated cell to a primitive cell state that recapitulates, in many aspects, features of embryonic cells. This review explores the current knowledge of developmental mechanisms that are essential for embryonic mouse mammary gland development, with a particular focus on genes and signaling pathway components that are essential for the induction, morphogenesis, and lineage specification of the mammary gland. The roles of these same genes and signaling pathways in mammary gland or breast tumorigenesis and metastasis are then summarized. Strikingly, key embryonic developmental pathways are often reactivated or dysregulated during tumorigenesis and metastasis in processes such as aberrant proliferation, epithelial-to-mesenchymal transition (EMT), and stem cell potency which affects cellular lineage hierarchy. These observations are in line with findings from recent studies using lineage tracing as well as bulk- and single-cell transcriptomics that have uncovered features of embryonic cells in cancer and metastasis through the identification of cell types, cell states and characterisation of their dynamic changes. Given the many overlapping features and similarities of the molecular signatures of normal development and cancer, embryonic molecular signatures could be useful prognostic markers for cancer. In this way, the study of embryonic development will continue to complement the understanding of the mechanisms of cancer and aid in the discovery of novel therapeutic targets and strategies.
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36
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Giuli MV, Mancusi A, Giuliani E, Screpanti I, Checquolo S. Notch signaling in female cancers: a multifaceted node to overcome drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:805-836. [PMID: 35582386 PMCID: PMC8992449 DOI: 10.20517/cdr.2021.53] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022]
Abstract
Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.
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Affiliation(s)
- Maria V Giuli
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Angelica Mancusi
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Eugenia Giuliani
- Scientific Direction, San Gallicano Dermatological Institute IRCCS, Rome 00144, Italy
| | - Isabella Screpanti
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina 04100, Italy.,Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy
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Shaikh S, Shaikh J, Naba YS, Doke K, Ahmed K, Yusufi M. Curcumin: reclaiming the lost ground against cancer resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:298-320. [PMID: 35582033 PMCID: PMC9019276 DOI: 10.20517/cdr.2020.92] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/15/2020] [Accepted: 01/06/2021] [Indexed: 12/11/2022]
Abstract
Curcumin, a polyphenol, has a wide range of biological properties such as anticancer, antibacterial, antitubercular, cardioprotective and neuroprotective. Moreover, the anti-proliferative activities of Curcumin have been widely studied against several types of cancers due to its ability to target multiple pathways in cancer. Although Curcumin exhibited potent anticancer activity, its clinical use is limited due to its poor water solubility and faster metabolism. Hence, there is an immense interest among researchers to develop potent, water-soluble, and metabolically stable Curcumin analogs for cancer treatment. While drug resistance remains a major problem in cancer therapy that renders current chemotherapy ineffective, curcumin has shown promise to overcome the resistance and re-sensitize cancer to chemotherapeutic drugs in many studies. In the present review, we are summarizing the role of curcumin in controlling the proliferation of drug-resistant cancers and development of curcumin-based therapeutic applications from cell culture studies up to clinical trials.
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Affiliation(s)
- Siraj Shaikh
- Post-Graduate Department of Chemistry and Research Center, Abeda Inamdar Senior College of Arts, Science and Commerce (Affiliated to SPPU), Pune 411001, India.,Advanced Scientific Research Laboratory, Azam Campus, Pune 411001, India
| | - Javed Shaikh
- Post-Graduate Department of Chemistry and Research Center, Abeda Inamdar Senior College of Arts, Science and Commerce (Affiliated to SPPU), Pune 411001, India.,Advanced Scientific Research Laboratory, Azam Campus, Pune 411001, India
| | - Yusufi Sadia Naba
- Post-Graduate Department of Chemistry and Research Center, Abeda Inamdar Senior College of Arts, Science and Commerce (Affiliated to SPPU), Pune 411001, India
| | - Kailas Doke
- Post-Graduate Department of Chemistry and Research Center, Abeda Inamdar Senior College of Arts, Science and Commerce (Affiliated to SPPU), Pune 411001, India.,Advanced Scientific Research Laboratory, Azam Campus, Pune 411001, India
| | - Khursheed Ahmed
- Post-Graduate Department of Chemistry and Research Center, Abeda Inamdar Senior College of Arts, Science and Commerce (Affiliated to SPPU), Pune 411001, India.,Advanced Scientific Research Laboratory, Azam Campus, Pune 411001, India
| | - Mujahid Yusufi
- Post-Graduate Department of Chemistry and Research Center, Abeda Inamdar Senior College of Arts, Science and Commerce (Affiliated to SPPU), Pune 411001, India.,Advanced Scientific Research Laboratory, Azam Campus, Pune 411001, India
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Melis M, Tang XH, Mai K, Gudas LJ, Trasino SE. Fenretinide Reduces Intestinal Mucin-2-Positive Goblet Cells in Chronic Alcohol Abuse. Pharmacology 2022; 107:406-416. [PMID: 35551126 DOI: 10.1159/000524386] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 03/27/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Alcohol-induced thickening of the gut mucosal layer and increased expression of goblet cell gel-forming mucins, such as mucin-2 (MUC2) are associated with disruptions to the gut barrier in alcoholic liver disease (ALD). Interest in drugs that can target gut mucins in ALD has grown; however to date, no studies have examined the properties of drugs on expression of gut mucins in models of ALD. We previously demonstrated that at 10 mg/kg/day, the drug fenretinide (N-[4-hydroxyphenyl] retinamide [Fen]), a synthetic retinoid, mitigates alcohol-associated damage to the gut barrier and liver injury in a murine model of ALD. METHODS In this study, we specifically sought to examine the effects of Fen on gut goblet cells, and expression of mucins, including MUC2 using a 25-day Lieber-DeCarli model of chronic alcohol intake. RESULTS Our results show that chronic alcohol intake increased gut-mucosal thickening, goblet cell numbers, and mRNA and protein expression of MUC2 in both the ileum and colon. Alcohol intake was associated with marked decreases in ileal and colonic Notch signaling, levels of Notch ligands Dll1 and Dll4, and increases in the expression of Notch-associated genes indispensable for goblet cell specification, including Math1 and Spdef. Interestingly, ileal and colonic expression of KLF4, which is involved in terminal differentiation of goblet cells, was reduced in mice chronically fed alcohol. Coadministration of alcohol with Fen at 10 mg/kg/day significantly reduced alcohol-associated increases in ileal and colonic mucosal thickening, ileal Muc2, colonic Muc2, Muc5ac and Muc6 mRNAs, and goblet cell numbers. We also found that Fen strongly prevented alcohol-mediated suppression of the Notch ligand Dll1, Notch signaling, and alcohol-induced increases in expression of Notch-associated goblet cell specification genes in both the ileum and colon. In the absence of alcohol, Fen treatments alone at 10 mg/kg/day had no effects on any of the goblet cell-related endpoints. CONCLUSION These data show for the first time that the drug Fen possesses mucosal layer-modulating properties in response to chronic alcohol abuse. These data warrant further preclinical examination of Fen given the need for anti-ALD drugs and emerging evidence of a role for intestinal goblet cell mucins in the progression of ALD.
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Affiliation(s)
- Marta Melis
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA
| | - Xiao-Han Tang
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA
| | - Karen Mai
- Nutrition Program, Hunter College, City University of New York, New York, New York, USA
| | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA
| | - Steven E Trasino
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA.,Nutrition Program, Hunter College, City University of New York, New York, New York, USA
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Shen W, Zhou Q, Peng C, Li J, Yuan Q, Zhu H, Zhao M, Jiang X, Liu W, Ren C. FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies. Front Oncol 2022; 12:880077. [PMID: 35515121 PMCID: PMC9063462 DOI: 10.3389/fonc.2022.880077] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/15/2022] [Indexed: 12/13/2022] Open
Abstract
FBXW7, a member of the F-box protein family within the ubiquitin–proteasome system, performs an indispensable role in orchestrating cellular processes through ubiquitination and degradation of its substrates, such as c-MYC, mTOR, MCL-1, Notch, and cyclin E. Mainly functioning as a tumor suppressor, inactivation of FBXW7 induces the aberrations of its downstream pathway, resulting in the occurrence of diseases especially tumorigenesis. Here, we decipher the relationship between FBXW7 and the hallmarks of cancer and discuss the underlying mechanisms. Considering the interplay of cancer hallmarks, we propose several prospective strategies for circumventing the deficits of therapeutic resistance and complete cure of cancer patients.
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Affiliation(s)
- Wenyue Shen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Quanwei Zhou
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chenxi Peng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jiaheng Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qizhi Yuan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hecheng Zhu
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China.,Changsha Kexin Cancer Hospital, Changsha, China
| | - Ming Zhao
- Changsha Kexin Cancer Hospital, Changsha, China
| | - Xingjun Jiang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Weidong Liu
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, China
| | - Caiping Ren
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, China
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Grazioli P, Orlando A, Giordano N, Noce C, Peruzzi G, Abdollahzadeh B, Screpanti I, Campese AF. Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia. Front Immunol 2022; 13:809261. [PMID: 35444651 PMCID: PMC9013886 DOI: 10.3389/fimmu.2022.809261] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 03/09/2022] [Indexed: 12/28/2022] Open
Abstract
Notch receptors deeply influence T-cell development and differentiation, and their dysregulation represents a frequent causative event in "T-cell acute lymphoblastic leukemia" (T-ALL). "Myeloid-derived suppressor cells" (MDSCs) inhibit host immune responses in the tumor environment, favoring cancer progression, as reported in solid and hematologic tumors, with the notable exception of T-ALL. Here, we prove that Notch-signaling deregulation in immature T cells promotes CD11b+Gr-1+ MDSCs in the Notch3-transgenic murine model of T-ALL. Indeed, aberrant T cells from these mice can induce MDSCs in vitro, as well as in immunodeficient hosts. Conversely, anti-Gr1-mediated depletion of MDSCs in T-ALL-bearing mice reduces proliferation and expansion of malignant T cells. Interestingly, the coculture with Notch-dependent T-ALL cell lines, sustains the induction of human CD14+HLA-DRlow/neg MDSCs from healthy-donor PBMCs that are impaired upon exposure to gamma-secretase inhibitors. Notch-independent T-ALL cells do not induce MDSCs, suggesting that Notch-signaling activation is crucial for this process. Finally, in both murine and human models, IL-6 mediates MDSC induction, which is significantly reversed by treatment with neutralizing antibodies. Overall, our results unveil a novel role of Notch-deregulated T cells in modifying the T-ALL environment and represent a strong premise for the clinical assessment of MDSCs in T-ALL patients.
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Affiliation(s)
- Paola Grazioli
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Andrea Orlando
- Department of Molecular Medicine, Sapienza University, Rome, Italy.,Center for Life Nano- and Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Nike Giordano
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Claudia Noce
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Giovanna Peruzzi
- Center for Life Nano- and Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
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Ho MT, Lu J, Vazquez-Pianzola P, Suter B. α-Phenylalanyl tRNA synthetase competes with Notch signaling through its N-terminal domain. PLoS Genet 2022; 18:e1010185. [PMID: 35486661 PMCID: PMC9094542 DOI: 10.1371/journal.pgen.1010185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 05/11/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023] Open
Abstract
The alpha subunit of the cytoplasmic Phenylalanyl tRNA synthetase (α-PheRS, FARSA in humans) displays cell growth and proliferation activities and its elevated levels can induce cell fate changes and tumor-like phenotypes that are neither dependent on the canonical function of charging tRNAPhe with phenylalanine nor on stimulating general translation. In intestinal stem cells of Drosophila midguts, α-PheRS levels are naturally slightly elevated and human FARSA mRNA levels are elevated in multiple cancers. In the Drosophila midgut model, elevated α-PheRS levels caused the accumulation of many additional proliferating cells resembling intestinal stem cells (ISCs) and enteroblasts (EBs). This phenotype partially resembles the tumor-like phenotype described as Notch RNAi phenotype for the same cells. Genetic interactions between α-PheRS and Notch suggest that their activities neutralize each other and that elevated α-PheRS levels attenuate Notch signaling when Notch induces differentiation into enterocytes, type II neuroblast stem cell proliferation, or transcription of a Notch reporter. These non-canonical functions all map to the N-terminal part of α-PheRS which accumulates naturally in the intestine. This truncated version of α-PheRS (α-S) also localizes to nuclei and displays weak sequence similarity to the Notch intracellular domain (NICD), suggesting that α-S might compete with the NICD for binding to a common target. Supporting this hypothesis, the tryptophan (W) residue reported to be key for the interaction between the NICD and the Su(H) BTD domain is not only conserved in α-PheRS and α-S, but also essential for attenuating Notch signaling. Aminoacyl tRNA synthetases charge tRNAs with their cognate amino acid to ensure proper decoding of the genetic code during translation. Independent of its aminoacylation function, the alpha subunit of Drosophila cytoplasmic Phenylalanyl tRNA synthetase (α-PheRS, FARSA in humans) has an additional activity that promotes growth and proliferation. Here we describe that elevated α-PheRS levels also induce cell fate changes and tumorous phenotypes in Drosophila midguts. Excessive proliferating cells with stem and progenitor cell characteristics accumulate and the composition of the terminally differentiated cells changes, too. This phenotype together with observed genetic interactions between α-PheRS and Notch levels show that α-PheRS counteracts Notch signaling in many different tissues and developmental stages. This novel activity of α-PheRS maps to its N-terminal part, which is naturally produced. The fragment contains a DNA binding domain, translocates into nuclei, and displays essential similarities to a Notch domain that binds to the downstream transcription factor. This suggests that it might be competing with Notch for binding to a common target. Not only because Notch plays important roles in many tumors, but also because FARSA mRNA levels are considerably upregulated in many tumors, this novel activity deserves more attention for cancer research.
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Affiliation(s)
- Manh Tin Ho
- Institute of Cell Biology, University of Bern, Bern, Switzerland
| | - Jiongming Lu
- Institute of Cell Biology, University of Bern, Bern, Switzerland
| | | | - Beat Suter
- Institute of Cell Biology, University of Bern, Bern, Switzerland
- * E-mail:
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Saha T, Lukong KE. Breast Cancer Stem-Like Cells in Drug Resistance: A Review of Mechanisms and Novel Therapeutic Strategies to Overcome Drug Resistance. Front Oncol 2022; 12:856974. [PMID: 35392236 PMCID: PMC8979779 DOI: 10.3389/fonc.2022.856974] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.
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Affiliation(s)
- Taniya Saha
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kiven Erique Lukong
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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