1
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Wen J, Geng L, Wang R, Zhang X, Sui Y, Liu X, Han X. Carboxylesterase 1 regulates peroxisome proliferator-activated receptor gamma to inhibit the growth and metastasis of breast cancer cells. J Mol Histol 2025; 56:167. [PMID: 40418235 DOI: 10.1007/s10735-025-10446-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 05/01/2025] [Indexed: 05/27/2025]
Abstract
Breast cancer is a common malignancy in women, and it has an absence of effective therapies. Carboxylesterase 1 (CES1), a member of the carboxylesterase family, has anti-tumor properties in several types of cancer. However, the function of CES1 in breast cancer remains unclear. Peroxisome proliferator-activated receptor gamma (PPARG) is a downstream regulator of CES1 and exhibits anti-breast cancer properties. Both CES1 and PPARG were downregulated in breast cancer tissues. Low CES1 and PPARG expression were linked to poorer breast cancer survival. We constructed CES1 knockdown and overexpression models of breast cancer cells by CES1 overexpressing plasmids and plasmids containing short hairpin RNA. High expression of CES1 inhibited breast cancer cell proliferation, evidenced by diminished cell viability, decreased DNA replication, and G1 phase arrest. CES1 overexpression decreased the protein levels of CDK2, CDK6 and cyclin B1 in breast cancer cells. CES1 inhibited the Bcl-2/Bax axis and increased Cleaved caspase-3 levels. Transwell assays showed that CES1 inhibited cell migration and invasion. CES1 increased E-cadherin protein expression and decreased Vimentin protein expression. CES1 knockdown facilitated the proliferation, migration, and invasion of breast cancer cells. CES1 was found to regulate PPARG expression in breast cancer cells positively. We transfected PPARG-interfering plasmids into breast cancer cells with CES1 overexpression. Inhibition of PPARG abrogated the anti-growth and anti-metastasis functions of CES1 in breast cancer cells. This study elucidates that CES1 inhibits the malignant progression of breast cancer by up-regulating the expression of PPARG.
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Affiliation(s)
- Jingli Wen
- Department of Oncology, Dongying People's Hospital, 317 Nanyi Road, Dongying, 257091, Shandong, China
| | - Lei Geng
- Department of Oncology, Dongying People's Hospital, 317 Nanyi Road, Dongying, 257091, Shandong, China
| | - Ruohan Wang
- Department of Pathology, Dongying People's Hospital, Dongying, 257091, Shandong, China
| | - Xiaolei Zhang
- Department of Oncology, Dongying People's Hospital, 317 Nanyi Road, Dongying, 257091, Shandong, China
| | - Yanmin Sui
- Department of Oncology, Dongying People's Hospital, 317 Nanyi Road, Dongying, 257091, Shandong, China
| | - Xiaofang Liu
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, 257091, Shandong, China
| | - Xin Han
- Department of Oncology, Dongying People's Hospital, 317 Nanyi Road, Dongying, 257091, Shandong, China.
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2
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Pitimontol P, Kongkiatpaiboon S, Worakhunpiset S, Reamtong O, Kosoltanapiwat N, Tantrakarnapa K, Mingkhwan R, Kiangkoo N, Limpanont Y. Inhibition activity of Artemisia vulgaris L. on Bhas 42 cell transformation. Sci Rep 2025; 15:18028. [PMID: 40410249 PMCID: PMC12102394 DOI: 10.1038/s41598-025-03179-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 05/19/2025] [Indexed: 05/25/2025] Open
Abstract
Several factors can contribute to cancer development. Various methods are in use for cancer treatment, although their complications can be a cause of concern. Artemisia vulgaris L. is a medicinal herb proposed for treating several diseases, including cancer. This study investigated the inhibition activity of A. vulgaris on Bhas 42, a cell used to evaluate the carcinogenic potential of chemicals due to its ability to recapitulate to some extent of the multi-stage cell transformation process. Ethanolic extract of A. vulgaris was used to examine cytotoxicity and transformation inhibition activity on Bhas 42. Bhas 42 cells were induced by a cancer stimulator, 3-methylcholanthrene (MCA) or cancer promotor, 12-O-tetradecanoylphorbol-13-acetate (TPA), with and without A.vulgaris at various concentrations and date of addition. A. vulgaris can inhibit Bhas 42 cell transformation due to its smaller proportion of the transformed cells than those treated with only MCA or TPA. The most effective transformed foci inhibition condition was selected for proteomic assay. The proteomic study results also showed that the proteins related to the regulation of cancer cells, such as cancer development, proliferation, migration, transformation, and invasion of A. vulgaris treated groups, were dysregulated. Studies on the effects of A. vulgaris extract showed its ability to inhibit the transformation to cancer cells. However, further studies are required to understand these mechanisms better.
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Affiliation(s)
- Paweena Pitimontol
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Sumet Kongkiatpaiboon
- Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University (Rangsit Campus), Pathumthani, 12121, Thailand
- Thammasat University Research Unit in Cannabis and Herbal Products Innovation, Thammasat University (Rangsit Campus), Pathum Thani, 12121, Thailand
| | - Suwalee Worakhunpiset
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Onrapak Reamtong
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Nathamon Kosoltanapiwat
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Kraichat Tantrakarnapa
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Rachaneekorn Mingkhwan
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Nuttapohn Kiangkoo
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand
| | - Yanin Limpanont
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchavithi Rd, Bangkok, 10400, Thailand.
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3
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Bose S, Das S, Maity S, Raychaudhuri D, Banerjee T, Paul M, Mukhopadhyay A, Chakrabarti O, Chakrabarti S. Androgen receptor plays critical role in regulating cervical cancer cell migration. Mol Cell Endocrinol 2025:112583. [PMID: 40409531 DOI: 10.1016/j.mce.2025.112583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 04/23/2025] [Accepted: 05/20/2025] [Indexed: 05/25/2025]
Abstract
Cervical cancer (CC) is the second most common cancer among women in India and the fourth worldwide. While major genes and pathways have been studied, further research is needed to identify newer candidates for targeted therapy in metastatic disease. This study used a graph-theory-based network analysis to identify important interacting proteins (IIPs) with maximum connectivity, high centrality scores, and significant global and local network perturbation scores. Among the identified IIPs, the Androgen receptor (AR) emerged as one of the crucial yet understudied regulator in cervical cancer. Patient samples, ex vivo, and in vitro experiments showed significant downregulation of AR in cervical cancer. Ligand-dependent overexpression of AR reduced cancer cell migration while failed to induce apoptosis in CC cell lines. Downregulation of mesenchymal markers and restoration of epithelial markers upon exogenous expression of AR suggested its potential in reversing invasive properties of cervical cancer cells. AR overexpression followed by activation upregulated its downstream target PTEN and downregulated pPI3K levels, which in turn restored GSK3β activity by interfering with AKT phosphorylation, probably leading to degradation of mesenchymal markers in cervical cancer cells. Further studies showed that AR reduced cell motility by hindering focal adhesion formation and Actin filament assembly. An increased G-Actin ratio suggested AR disrupted cytoskeletal dynamics through altering the RhoA/ROCK1/LIMK1/CFL1 pathway eventually impeding cervical cancer cell spread.
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Affiliation(s)
- Sarpita Bose
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata 700091, WB, India
| | - Subhrangshu Das
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata 700091, WB, India
| | - Sebabrata Maity
- Biophysics and Structural Genomics Ddivision, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata - 700064, India; Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Deblina Raychaudhuri
- Division of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata 700091, WB, India
| | - Tania Banerjee
- Division of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata 700091, WB, India
| | - Madhurima Paul
- Division of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata 700091, WB, India
| | - Asima Mukhopadhyay
- Department of Gynecologic Oncosurgery, Tata Medical Center,14, Major Arterial Road (E-W), Kolkata 700160; Kolkata Gynecological Oncology Trials and Translational Research Group (Kolgotrg), DD 92, Street no 271, Newtown AA1, Kolkata 700156
| | - Oishee Chakrabarti
- Biophysics and Structural Genomics Ddivision, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata - 700064, India; Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Saikat Chakrabarti
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, IICB TRUE Campus, CN-6, Sector 5, Salt Lake, Kolkata 700091, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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4
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Wang H, Ardila C, Jindal A, Aggarwal V, Wang W, Vande Geest J, Jiang Y, Xing J, Sant S. Protrusion force and cell-cell adhesion-induced polarity alignment govern collective migration modes. Biophys J 2025; 124:1674-1692. [PMID: 40235119 DOI: 10.1016/j.bpj.2025.04.010] [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: 09/28/2024] [Revised: 02/28/2025] [Accepted: 04/10/2025] [Indexed: 04/17/2025] Open
Abstract
Collective migration refers to the coordinated movement of cells as a single unit during migration. Although collective migration enhances invasive and metastatic potential in cancer, the mechanisms driving this behavior and regulating tumor migration plasticity remain poorly understood. This study provides a mechanistic model explaining the emergence of different modes of collective migration under hypoxia-induced secretome. We focus on the interplay between cellular protrusion force and cell-cell adhesion using collectively migrating three-dimensional microtumors as models with well-defined microenvironments. Large microtumors show directional migration due to intrinsic hypoxia, whereas small microtumors exhibit radial migration when exposed to hypoxic secretome. Here, we developed an in silico multi-scale microtumor model based on the cellular Potts model and implemented in CompuCell3D to elucidate underlying mechanisms. We identified distinct migration modes within specific regions of protrusion force and cell-cell adhesion parameter space and studied these modes using in vitro experimental microtumor models. We show that sufficient cellular protrusion force is crucial for radial and directional collective microtumor migration. Radial migration emerges when sufficient cellular protrusion force is generated, driving neighboring cells to move collectively in diverse directions. Within migrating tumors, strong cell-cell adhesion enhances the alignment of cell polarity, breaking the symmetric angular distribution of protrusion forces and leading to directional microtumor migration. The integrated results from the experimental and computational models provide fundamental insights into collective migration in response to different microenvironmental stimuli. Our computational and experimental models can adapt to various scenarios, providing valuable insights into cancer migration mechanisms.
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Affiliation(s)
- Huijing Wang
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Catalina Ardila
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ajita Jindal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Vaishali Aggarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Weikang Wang
- Institute of Theoretical Physics, Chinese Academy of Sciences, Beijing, China; School of Physical Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Jonathan Vande Geest
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yi Jiang
- Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia
| | - Jianhua Xing
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, Pennsylvania; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Shilpa Sant
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmaceutical Sciences, Retzky College of Pharmacy, University of Illinois Chicago, Chicago, Illinois.
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5
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Ray SK, Mukherjee S. Mechanical factors in the breast cancer microenvironment: Emphasizing functional adaptation. Biochem Biophys Res Commun 2025; 771:152048. [PMID: 40412051 DOI: 10.1016/j.bbrc.2025.152048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 05/11/2025] [Accepted: 05/17/2025] [Indexed: 05/27/2025]
Abstract
Breast cancer cells can disrupt microenvironments and mechanical balance, leading to significant changes in tissues and alterations in cellular signaling pathways. Recent researches explore advancements in breast cancer cell mechanobiology, focusing on the interaction between cells and their microenvironment and the regulation of cellular behavior through mechanical stress. Factors include the rigidity of the surrounding surface, the substrate's chemical and topological patterns, and the differences between two-dimensional and three-dimensional cultures. Mechanical loading scenarios, such as tensile stretch, compression, and flow-induced shear, are also reviewed to prevent metastasis. However, breast cancer does not follow a strict pattern, and its adaptability facilitated by specific proteins that form the mechanical network. These proteins exhibit modified expression in breast cancer or direct participation in cancer advancement. Directing therapeutic efforts towards the mechanical system may result in more effective therapies in the future. However, this complex task requires caution to prevent potential adverse reactions. The substrate microenvironment and mechanical signals will collaborate to regulate cancer cell advancement and spread. Mechanotransduction, the process by which cells read physical cues, plays a crucial role in breast cancer. Three mechanical stressors, stiffness, interstitial fluid pressure, and solid stress, have been supported as mechanical modifiers in breast cancer. This review presents the potential of directing therapeutic interventions toward the mechanical program to treat cancer and discusses the associated difficulties and limitations.
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Affiliation(s)
- Suman Kumar Ray
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, 462020, India
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, 462020, India.
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6
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Roncoroni R, Baci D, Cucchiara M, de Vito A, Gallazzi M, Palano MT, Olmeo F, Rubuano C, Giannatiempo A, Monti L, Bombelli R, Mercatelli D, Finzi G, Franzi F, Rosa SL, Noonan DM, Bassani B, Mortara L, Bruno A, Acquati F. The human RNASET2 alarmin-like molecule differentially affects prostate cancer cells behavior in both cell autonomous and non-cell autonomous manners. J Transl Med 2025; 23:560. [PMID: 40389981 PMCID: PMC12090474 DOI: 10.1186/s12967-025-06540-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 04/25/2025] [Indexed: 05/21/2025] Open
Abstract
The identification of molecules that make cancer cells detectable by the immune system represents a major challenge in tumor immunology. Alarmins, endogenous, stress-induced molecules, serve as early warning signals triggering immune responses. The human RNASET2 protein has demonstrated both oncosuppressive and immunoregulatory functions across various cancer types, yet its role as an oncosuppressor or alarmin-like molecule in prostate cancer (PCa) is unexplored. Here, we investigated the effects of the human RNASET2 alarmin in two different human PCa cell lines focusing on cell proliferation, colony formation, adhesion, migration rates, and release of soluble immune-modulatory factors. In vivo studies were also carried out on nude mice to assess the immune regulatory impact. Our findings indicate that RNASET2 overexpression reduced cell proliferation and colony formation in 22Rv1 cells, through downregulation of cyclin D1. RNASET2 overexpression in 22Rv1 cells was also associated with decreased levels of TWIST, CTNNB1, YAP, and MMP-9. By contrast, PC-3 cells were largely unresponsive to RNASET2. RNASET2 overexpression also promoted the release of soluble factors related to monocyte/macrophage recruitment/activation and cytokines/chemokines, linked to immune cell-mediated anti-tumor responses. This effect was more pronounced in RNASET2-overexpressing 22Rv1 cells and involved both innate (NK cells, dendritic cells) and adaptive (T cells) immune activation, compared to PC-3 cells. RNASET2 overexpression also affected the cytoskeletal organization in both PCa models. RNASET2 overexpression in vivo induced a shift toward M1-like macrophage polarization pattern, while decreasing the M2-like polarization in mice challenged with 22Rv1 cells, indicating a potential tumor-suppressive role in PCa. Finally, silencing of RNASET2 in THP-1 macrophages unveiled their phagocytic activities against PCa cells. Our findings underscore the RNASET2's dual functionality, acting through both cell-autonomous and non-cell autonomous mechanisms in PCa in vitro and in vivo models and suggest its potential as a therapeutic target in a subset of PCa.
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Affiliation(s)
- Rossella Roncoroni
- Laboratory of Human Genetics, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Denisa Baci
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Martina Cucchiara
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Annarosaria de Vito
- Laboratory of Human Genetics, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Matteo Gallazzi
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Maria Teresa Palano
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Francesca Olmeo
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Cristian Rubuano
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Alessandra Giannatiempo
- Laboratory of Human Genetics, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Laura Monti
- Laboratory of Human Genetics, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Raffaella Bombelli
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Daniele Mercatelli
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Giovanna Finzi
- Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Francesca Franzi
- Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
- Unit of Pathology, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy
- Hereditary Cancer Research Center, University of Insubria, Varese, Italy
| | - Douglas M Noonan
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Unit of Molecular Pathology, Biochemistry, and Immunology IRCCS MultiMedica, Milan, Italy
| | - Barbara Bassani
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy
| | - Lorenzo Mortara
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
- Unit of Molecular Pathology, Biochemistry, and Immunology IRCCS MultiMedica, Milan, Italy
| | - Antonino Bruno
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, IRCCS MultiMedica, Milan, Italy.
| | - Francesco Acquati
- Laboratory of Human Genetics, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
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7
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Duff D, Gargan S, Long A. Non-muscle myosin heavy chain IIA regulates cell morphology, stress fibre structure, and cell migration in FLO-1 oesophageal adenocarcinoma cells. Hum Cell 2025; 38:80. [PMID: 40164920 PMCID: PMC11958448 DOI: 10.1007/s13577-025-01196-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 02/27/2025] [Indexed: 04/02/2025]
Abstract
The incidence of oesophageal adenocarcinoma (OAC) is increasing at a rapid rate in Western countries. Early oesophageal cancer is often asymptomatic and metastatic disease is common at presentation leading to poor prognosis and survival rates. Cell migration is tightly controlled in the healthy cell but can become dysregulated in diseases such as OAC where increased cell motility and migration can contribute to metastasis. We investigated the role of an actin-based molecular motor, non-muscle myosin heavy chain IIA (NMHCIIA) in the migratory capacity of oesophageal adenocarcinoma cells. Immunofluorescence microscopy and ratiometric imaging demonstrated that NMHCIIA co-localises with F-actin at the leading edge and retracting rear of migrating FLO-1 OAC cells. siRNA-mediated depletion of NMHCIIA from FLO-1 cells altered cell morphology, gave rise to an increased number of stress fibre like structures and reduced FLO-1 cell migration. These findings suggest that NMHCIIA influences FLO-1 cell migration by regulating F-actin dynamics and the actin cytoskeleton, providing insight into the mechanisms of migration employed by OAC cells and identifying NMHCIIA as a potential therapeutic target for this disease.
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Affiliation(s)
- Deirdre Duff
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Siobhan Gargan
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Aideen Long
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
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8
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Ragazzini G, Mescola A, Tassinari R, Gallerani A, Zannini C, Di Rosa D, Cavallini C, Marcuzzi M, Taglioli V, Bighi B, Ettari R, Zappavigna V, Ventura C, Alessandrini A, Corsi L. A Benzodiazepine-Derived Molecule That Interferes with the Bio-Mechanical Properties of Glioblastoma-Astrocytoma Cells Altering Their Proliferation and Migration. Int J Mol Sci 2025; 26:2767. [PMID: 40141408 PMCID: PMC11943291 DOI: 10.3390/ijms26062767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Glioblastoma multiforme (grade IV glioma) is characterized by a high invasive potential, making surgical intervention extremely challenging and patient survival very limited. Current pharmacological approaches show, at best, slight improvements in the therapy against this type of tumor. Microtubules are often the target of antitumoral drugs, and specific drugs affecting their dynamics by acting on microtubule-associated proteins (MAPs) without producing their depolymerization could affect both glioma cell migration/invasion and cell proliferation. Here, we analyzed on a cellular model of glioblastoma multiforme, the effect of a molecule (1-(4-amino-3,5-dimethylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4h2,3-benzodiazepin-4-one, hereafter named 1g) which was shown to act as a cytostatic drug in other cell types by affecting microtubule dynamics. We found that the molecule acts also as a migration suppressor by inducing a loss of cell polarity. We characterized the mechanics of U87MG cell aggregates exposed to 1g by different biophysical techniques. We considered both 3D aggregates and 2D cell cultures, testing substrates of different stiffness. We established that this molecule produces a decrease of cell spheroid contractility and it impairs 3D cell invasion. At the same time, in the case of isolated cells, 1g selectively produces an almost instantaneous loss of cell polarity blocking migration and it also produces a disorganization of the mitotic spindle when cells reach mitosis, leading to frequent mitotic slippage events followed by cell death. We can state that the studied molecule produces similar effects to other molecules that are known to affect the dynamics of microtubules, but probably indirectly via microtubule-associated proteins (MAPs) and following different biochemical pathways. Consistently, we report evidence that, regarding its effect on cell morphology, this molecule shows a specificity for some cell types such as glioma cells. Interestingly, being a molecule derived from a benzodiazepine, the 1g chemical structure could allow this molecule to easily cross the blood-brain barrier. Thanks to its chemical/physical properties, the studied molecule could be a promising new drug for the specific treatment of GBM.
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Affiliation(s)
- Gregorio Ragazzini
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Andrea Mescola
- CNR-Nanoscience Institute-S3, Via Campi 213/A, 41125 Modena, Italy;
| | - Riccardo Tassinari
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Alessia Gallerani
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
| | - Chiara Zannini
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Domenico Di Rosa
- Lab of Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, SaIA, University of Salerno, 84081 Baronissi, Italy;
| | - Claudia Cavallini
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Martina Marcuzzi
- Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 49, 40126 Bologna, Italy;
| | - Valentina Taglioli
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Beatrice Bighi
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
- CNR-Nanoscience Institute-S3, Via Campi 213/A, 41125 Modena, Italy;
| | - Roberta Ettari
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy;
| | - Vincenzo Zappavigna
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy;
| | - Carlo Ventura
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
- Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 49, 40126 Bologna, Italy;
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy
| | - Andrea Alessandrini
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
- CNR-Nanoscience Institute-S3, Via Campi 213/A, 41125 Modena, Italy;
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy
| | - Lorenzo Corsi
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy;
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy
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9
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Hemavathy N, Ranganathan S, Umashankar V, Jeyakanthan J. Computational Development of Allosteric Peptide Inhibitors Targeting LIM Kinases as a Novel Therapeutic Intervention. Cell Biochem Biophys 2025:10.1007/s12013-025-01718-1. [PMID: 40100341 DOI: 10.1007/s12013-025-01718-1] [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] [Accepted: 03/02/2025] [Indexed: 03/20/2025]
Abstract
LIM Kinases (LIMKs) have emerged as critical therapeutic targets in cancer research due to their central role in regulating cytoskeletal dynamics and cell motility via cofilin phosphorylation. Allosteric inhibitors, which bind outside the ATP-binding pocket, offer distinct advantages over ATP-competitive inhibitors, such as increased specificity, reduced off-target effects, and the ability to overcome resistance. This study investigates a series of novel tetrapeptides mimicking the binding mode of TH470, an allosteric LIMK inhibitor, using in silico docking and molecular dynamics simulations to identify potential lead compounds with high specificity, binding affinity, and favorable pharmacokinetic properties. Structural analyses revealed critical interactions between TH470 and LIMKs, particularly with conserved residues such as Thr405 (gatekeeper residue), Ile408 (hinge region), and Asp469 (XDFG motif), which are essential for stabilizing inhibitor binding. Molecular dynamics simulations confirmed the stability of TH470-LIMK1 and TH470-LIMK2 complexes, with lower RMS deviations and robust interaction patterns enhancing binding affinity. From the set of tetrapeptides mimicking TH470 binding mode, only YFYW, WPHW, and YWFP for LIMK1, and PYWG, FYWV, and WFVW for LIMK2 demonstrated high binding affinities, non-toxic profiles, and promising anti-cancer, anti-angiogenic, and anti-inflammatory properties. Among the studied peptides, LIMK1-YFYW and LIMK2-WFVW exhibited the most substantial binding affinities, supported by high hydrogen bond occupancy with key residues such as Ile416 and Thr405. The findings highlight the therapeutic potential of allosteric peptide inhibitors targeting LIMK-mediated pathways in cancer progression. The study underscores the importance of specific interactions with conserved LIMK residues, providing a foundation for further developing selective inhibitors to modulate actin dynamics and combat cancer-related processes.
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Affiliation(s)
- Nagarajan Hemavathy
- Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi, Tamil Nadu, India
| | | | - Vetrivel Umashankar
- Virology & Biotechnology/Bioinformatics Division, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India
| | - Jeyaraman Jeyakanthan
- Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi, Tamil Nadu, India.
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10
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Sun J, Hosen MB, Deng WM, Tian A. Epithelial Polarity Loss and Multilayer Formation: Insights Into Tumor Growth and Regulatory Mechanisms. Bioessays 2025; 47:e202400189. [PMID: 39737681 DOI: 10.1002/bies.202400189] [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: 08/03/2024] [Revised: 12/11/2024] [Accepted: 12/12/2024] [Indexed: 01/01/2025]
Abstract
Epithelial tissues serve as critical barriers in metazoan organisms, maintaining structural integrity and facilitating essential physiological functions. Epithelial cell polarity regulates mechanical properties, signaling, and transport, ensuring tissue organization and homeostasis. However, the barrier function is challenged by cell turnover during development and maintenance. To preserve tissue integrity while removing dying or unwanted cells, epithelial tissues employ cell extrusion. This process removes both dead and live cells from the epithelial layer, typically causing detached cells to undergo apoptosis. Transformed cells, however, often resist apoptosis, leading to multilayered structures and early carcinogenesis. Malignant cells may invade neighboring tissues. Loss of cell polarity can lead to multilayer formation, cell extrusion, and invasion. Recent studies indicate that multilayer formation in epithelial cells with polarity loss involves a mixture of wild-type and mutant cells, leading to apical or basal accumulation. The directionality of accumulation is regulated by mutations in polarity complex genes. This phenomenon, distinct from traditional apical or basal extrusion, exhibits similarities to the endophytic or exophytic growth observed in human tumors. This review explores the regulation and implications of these phenomena for tissue biology and disease pathology.
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Affiliation(s)
- Jie Sun
- Department of Biochemistry and Molecular Biology, Louisiana Cancer Research Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Md Biplob Hosen
- Department of Biochemistry and Molecular Biology, Louisiana Cancer Research Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Wu-Min Deng
- Department of Biochemistry and Molecular Biology, Louisiana Cancer Research Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Tulane Aging Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Aiguo Tian
- Department of Biochemistry and Molecular Biology, Louisiana Cancer Research Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Tulane Aging Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
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11
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Yu RY, Jiang WG, Martin TA. The WASP/WAVE Protein Family in Breast Cancer and Their Role in the Metastatic Cascade. Cancer Genomics Proteomics 2025; 22:166-187. [PMID: 39993807 PMCID: PMC11880927 DOI: 10.21873/cgp.20495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/04/2024] [Accepted: 12/18/2024] [Indexed: 02/26/2025] Open
Abstract
The Wiskott-Aldrich syndrome protein (WASP) and the WASP family verprolin-homologous protein (WAVE) family are essential molecules that connect GTPases to the actin cytoskeleton, thereby controlling actin polymerisation through the actin-related protein 2/3 complex. This control is crucial for forming actin-based membrane protrusions necessary for cell migration and invasion. The elevated expression of WASP/WAVE proteins in invasive breast cancer cells highlights their significant role in promoting cell motility and invasion. This review summarises the discovery, structural properties, and activation mechanisms of WASP/WAVE proteins, focuses on the contribution of the WASP/WAVE family to breast cancer invasion and migration, particularly synthesises the results of nearly a decade of research in this field since 2015. By exploring promising therapeutic strategies for breast cancer, including small molecule inhibitors and biological agents, this review stresses the potential for developing anticancer drugs that target the WASP/WAVE family and associated pathways, intending to improve the prognosis for patients with metastatic breast cancer.
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Affiliation(s)
- Rhiannon Yannan Yu
- Cardiff-China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff, U.K
| | - Wen G Jiang
- Cardiff-China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff, U.K
| | - Tracey A Martin
- Cardiff-China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff, U.K.
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12
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Ji Y, Lin Y, He J, Xie Y, An W, Luo X, Qiao X, Li Z. Research progress of mitochondria and cytoskeleton crosstalk in tumour development. Biochim Biophys Acta Rev Cancer 2025; 1880:189254. [PMID: 39732178 DOI: 10.1016/j.bbcan.2024.189254] [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: 07/11/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 12/30/2024]
Abstract
During tumour progression, organelle function undergoes dramatic changes, and crosstalk among organelles plays a significant role. Crosstalk between mitochondria and other organelles such as the endoplasmic reticulum and cytoskeleton has focussed attention on the mechanisms of tumourigenesis. This review demonstrates an overview of the molecular structure of the mitochondrial-cytoskeletal junction and its biological interactions. It also presents a detailed and comprehensive description of mitochondrial-cytoskeletal crosstalk in tumour occurrence and development, including tumour cell proliferation, apoptosis, autophagy, metabolic rearrangement, and metastasis. Finally, the application of crosstalk in tumour therapy, including drug combinations and chemoresistance, is discussed. This review offers a theoretical basis for establishing mitochondrial-cytoskeletal junctions as therapeutic targets, and offers novel insights into the future management of malignant tumours.
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Affiliation(s)
- Yue Ji
- Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China
| | - Yingchi Lin
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China; Provincial key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, China
| | - Jing He
- Department of Oral Implantology, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Diseases, Shenyang 110002, Liaoning Province, China
| | - Yuanyuan Xie
- Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China
| | - Wenmin An
- Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China
| | - Xinyu Luo
- Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China
| | - Xue Qiao
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China; Department of Central Laboratory, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China.
| | - Zhenning Li
- Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang 110002, Liaoning Province, China.
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13
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Kim MH, Park MK, Park HN, Ham SM, Lee H, Lee ST. Anti-PTK7 Monoclonal Antibodies Suppresses Oncogenic Phenotypes in Cellular and Xenograft Models of Triple-Negative Breast Cancer. Cells 2025; 14:181. [PMID: 39936972 PMCID: PMC11817174 DOI: 10.3390/cells14030181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/15/2025] [Accepted: 01/21/2025] [Indexed: 02/13/2025] Open
Abstract
Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase, is frequently upregulated in various cancers, including triple-negative breast cancer (TNBC), and is associated with poor clinical outcomes. Analysis of The Cancer Genome Atlas (TCGA) data confirmed that PTK7 mRNA expression is significantly higher in TNBC tumor tissues compared with adjacent normal tissues and non-TNBC breast cancer subtypes. Kaplan-Meier survival analysis demonstrated a strong correlation between high PTK7 expression and worse relapse-free survival in TNBC patients (HR = 1.46, p = 0.015). In vitro, anti-PTK7 monoclonal antibodies (mAbs) significantly reduced proliferation, wound healing, migration, and invasion in TNBC MDA-MB-231 cells. Ki-67 immunofluorescence assays revealed substantial decreases in cell proliferation following treatment with PTK7 mAbs (32-m, 43-m, 50-m, and 52-m). Moreover, actin polymerization, a critical process in cell migration and invasion, was markedly impaired upon PTK7 mAb treatment. In vivo, PTK7 mAbs significantly reduced tumor volume and weight in a TNBC xenograft mouse model compared with controls. Treated tumors exhibited decreased expression of Ki-67 and vimentin, indicating reduced proliferation and epithelial-to-mesenchymal transition. These findings highlight PTK7 as a promising therapeutic target in TNBC and demonstrate the potent anti-cancer effects of PTK7-neutralizing mAbs both in vitro and in vivo. Further exploration of PTK7-targeted therapies, including humanized mAbs and antibody-drug conjugates, is warranted to advance treatment strategies for PTK7-positive TNBC.
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Affiliation(s)
- Min Ho Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (M.H.K.); (H.N.P.); (S.M.H.)
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea;
- Department of Biomedical Science, Hwasung Medi-Science University, Hwaseong 18274, Republic of Korea
| | - Han Na Park
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (M.H.K.); (H.N.P.); (S.M.H.)
| | - Seung Min Ham
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (M.H.K.); (H.N.P.); (S.M.H.)
| | - Ho Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea;
| | - Seung-Taek Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (M.H.K.); (H.N.P.); (S.M.H.)
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14
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Qin H, Xu J, Yue Y, Chen M, Zhang Z, Xu P, Zheng Y, Zeng H, Weng J, Yang J, Yu F. Disulfidptosis-related gene signatures as prognostic biomarkers and predictors of immunotherapy response in HNSCC. Front Immunol 2025; 15:1456649. [PMID: 39896807 PMCID: PMC11782277 DOI: 10.3389/fimmu.2024.1456649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 12/12/2024] [Indexed: 02/04/2025] Open
Abstract
Background Disulfidptosis is a newly discovered form of cell death associated with tumorigenesis, particularly under oxidative stress and metabolic disorder conditions. Currently, the biological mechanisms of disulfidptosis-related genes (DRGs) in head and neck squamous cell carcinoma (HNSCC) remain unclear. Methods The study includes sections on methodologies, data sources, clinical data collection, subtype establishment, identification and analysis of differentially expressed genes, genetic variation, and the construction and validation of a DRG prognostic model. Various analyses are conducted, including the relationship between the risk scores model and clinicopathological features, immune status, immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), ESTIMATE, mRNAsi, and drug sensitivity. The study also covers single-cell analysis and DNA methylation analysis of DRGs, and the prediction of potential microRNA and long non-coding RNA target genes. Prognostic DRGs expression in HNSCC is validated through RT-qPCR and immunohistochemistry. The model's predictive capability is confirmed using external validation cohorts from GEO datasets and clinical tissue samples. The role of DSTN in HNSCC is further validated through gene knockout experiments. Results We identified four valuable genes (SLC3A2, NUBPL, ACTB, DSTN) and constructed a prognostic model, along with identifying two DRG-related subtypes. Analysis of the DRG risk score revealed that the low-risk group had a better prognosis compared to the high-risk group. Significant correlations were found between the DRG risk score and clinical features, immunotherapy response, drug sensitivity, and genes related to RNA epigenetic modifications. Low-risk HNSCC patients were identified as potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. A regulatory axis involving DSTN, hsa-miR-181c-5p, LUCAT1, and IGFL2-AS1 was constructed for HNSCC. RT-qPCR and IHC data further validated the upregulation of prognostic DRGs in HNSCC. The prognostic model demonstrated excellent predictive performance for the prognosis of HNSCC patients. Additionally, DSTN was significantly overexpressed in tumor cells; its knockdown inhibited tumor cell proliferation, migration, and invasion. Conclusion The prognostic model effectively predicts HNSCC outcomes, with better prognosis in the low-risk group. DSTN upregulation promotes tumor growth, and its knockout inhibits proliferation, migration, and invasion.
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Affiliation(s)
- Haotian Qin
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Juan Xu
- Department of Oncology, Chaohu Hospital of Anhui Medical University, Hefei, China
| | - Yaohang Yue
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Meiling Chen
- Operating Room, Peking University Shenzhen Hospital, Shenzhen, China
| | - Zheng Zhang
- Stomatological Center, Peking University Shenzhen Hospital, Shenzhen, China
| | - Panpan Xu
- Department of Otolaryngology Head and Neck Surgery, Chaohu Hospital of Anhui Medical University, Hefei, China
| | - Yan Zheng
- Department of Pathology, Chaohu Hospital of Anhui Medical University, Hefei, China
| | - Hui Zeng
- Department of Orthopedics, Medical Innovation Technology Transformation Center of Shenzhen Second People’s Hospital, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
| | - Jian Weng
- Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Jun Yang
- Department of Radiology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Fei Yu
- Department of Spine Surgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
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15
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Greaves GE, Pinna A, Taylor JM, Porter AE, Phillips CC. In Depth Mapping of Mesoporous Silica Nanoparticles in Malignant Glioma Cells Using Scattering-Type Scanning Near-Field Optical Microscopy. CHEMICAL & BIOMEDICAL IMAGING 2024; 2:842-849. [PMID: 39735833 PMCID: PMC11672216 DOI: 10.1021/cbmi.4c00053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 12/31/2024]
Abstract
Mesoporous silica nanoparticles (MSNPs) are promising nanomedicine vehicles due to their biocompatibility and ability to carry large cargoes. It is critical in nanomedicine development to be able to map their uptake in cells, including distinguishing surface associated MSNPs from those that are embedded or internalized into cells. Conventional nanoscale imaging techniques, such as electron and fluorescence microscopies, however, generally require the use of stains and labels to image both the biological material and the nanomedicines, which can interfere with the biological processes at play. We demonstrate an alternative imaging technique for investigating the interactions between cells and nanostructures, scattering-type scanning near-field optical microscopy (s-SNOM). s-SNOM combines the chemical sensitivity of infrared spectroscopy with the nanoscale spatial resolving power of scanning probe microscopy. We use the technique to chemically map the uptake of MSNPs in whole human glioblastoma cells and show that the simultaneously acquired topographical information can provide the embedding status of the MSNPs. We focus our imaging efforts on the lamellipodia and filopodia structures at the peripheries of the cells due to their significance in cancer invasiveness.
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Affiliation(s)
- George E. Greaves
- Experimental
Solid State Physics Group, Department of Physics, Imperial College, Exhibition Road, SW72AZ London, U.K.
| | - Alessandra Pinna
- Department
of Materials and London Centre for Nanotechnology, Imperial College, Exhibition
Road, SW72AZ London, U.K.
- School
of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, U.K.
- The
Francis Crick Institute, NW1 1AT London, U.K.
| | - Jonathan M. Taylor
- Department
of Materials and London Centre for Nanotechnology, Imperial College, Exhibition
Road, SW72AZ London, U.K.
| | - Alexandra E. Porter
- Department
of Materials and London Centre for Nanotechnology, Imperial College, Exhibition
Road, SW72AZ London, U.K.
| | - Chris C. Phillips
- Experimental
Solid State Physics Group, Department of Physics, Imperial College, Exhibition Road, SW72AZ London, U.K.
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16
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Adhikary S, Roy S, Budhathoki S, Chowdhury S, Stillwell A, Basnakian AG, Tackett A, Avaritt N, Milad M, Alam MA. Thiazole-fused androstenone and ethisterone derivatives: potent β- and γ-actin cytoskeleton inhibitors to treat melanoma tumors. RSC Med Chem 2024; 16:d4md00719k. [PMID: 39703801 PMCID: PMC11653411 DOI: 10.1039/d4md00719k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/01/2024] [Indexed: 12/21/2024] Open
Abstract
Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both in vitro and in vivo. These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin (ACTB) and γ-actin (ACTG1) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies.
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Affiliation(s)
- Sanjay Adhikary
- Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA
| | - Subrata Roy
- Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA
- Enviromental Sciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA
| | - Shailesh Budhathoki
- Molecular Biosciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA
| | - Siam Chowdhury
- Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA
- Computer Science, The College of Engineering and Computer Science, Arkansas State University Jonesboro AR 72468 USA
| | - Abbey Stillwell
- Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA
| | - Alexei G Basnakian
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences 4301 W. Markham St Little Rock AR 72205 USA
- Central Arkansas Veterans Healthcare System W. 7th St Little Rock AR 72205 USA
| | - Alan Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences Little Rock AR 72205 USA
| | - Nathan Avaritt
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences Little Rock AR 72205 USA
| | - Mohamed Milad
- The Department of Mathematics and Statistics, Arkansas State University Jonesboro AR 72467 USA
| | - Mohammad Abrar Alam
- Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA
- Enviromental Sciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA
- Molecular Biosciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA
- Arkansas Biosciences Institute, Arkansas State University Jonesboro AR 72467 USA
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17
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Li M, Cui H, Deng H, Deng Y, Yin S, Li T, Yuan T. Urolithin A promotes the degradation of TMSB10 to deformation F-actin in non-small-cell lung cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156109. [PMID: 39368341 DOI: 10.1016/j.phymed.2024.156109] [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: 02/16/2024] [Revised: 09/14/2024] [Accepted: 09/28/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Lung cancer is one of the most frequently diagnosed cancers and non-small-cell lung cancer (NSCLC) poses major diagnoses. Urolithin A (UA) is a natural compound produced by the gut microbiota through the metabolism of polyphenol ellagitannins (ETs) and ellagic acid (EA), which has been found to inhibit epithelial-mesenchymal transition (EMT) in lung cancer cell lines. However, the mechanism of UA function in NSCLC remains elusive. PROPOSE This study aimed to investigate the potential effectiveness of UA in NSCLC therapeutic and uncovering its underlying mechanisms. METHODS Effects of UA treatment, TMSB10 gene knockdown or overexpression on NSCLC cell phenotype were evaluated by availability, transwell assays. The downstream factors and pathways of UA were investigated by proteomics. TMSB10 expression in NSCLC tissues was detected by bioinformatics analysis as well as immunohistochemistry. Confocal imaging, GST pull-down and western blotting investigated the mechanism of UA induced TMSB10 degradation. RESULTS In the present study, we demonstrated that UA shows an inhibitory role in NSCLC cell proliferation, migration, and invasion. This inhibition is attributed to the accelerated degradation of TMSB10, a biomarker among various cancers, via the autophagy-lysosome pathway. Additionally, knocked down of TMSB10 showed a similar phenotype with UA treatment. The reduction of TMSB10 protein level following decreased ATP level inhibits the F-actin formation for cell migration, thereby disrupting the equilibrium between G-actin-TMSB10 and G-actin-ATP interactions in A549 cells. CONCLUSION Our results reveal that UA is potential for NSCLC therapeutics through reducing the protein level of TMSB10 to deformation the F-actin.
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Affiliation(s)
- Miaomiao Li
- School of Health, Jiangxi Normal University, Jiangxi Province Key Laboratory of Natural and Biomimetic Drugs Research, Nanchang, 330022, China; College of Life Science, Jiangxi Normal University, Nanchang, 330022, China
| | - Hao Cui
- College of Life Science, Jiangxi Normal University, Nanchang, 330022, China
| | - Huan Deng
- Rehabiliation Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China; Tumor Immunology Institute, Nanchang University, 330006, Nanchang, Jiangxi, China; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, 330031, Nanchang, Jiangxi, China
| | - Yanjuan Deng
- Rehabiliation Hospital, Jiangxi Medical College, Nanchang University, 330006, Nanchang, Jiangxi, China; Tumor Immunology Institute, Nanchang University, 330006, Nanchang, Jiangxi, China
| | - Sheng Yin
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China
| | - Tianzhi Li
- School of Health, Jiangxi Normal University, Jiangxi Province Key Laboratory of Natural and Biomimetic Drugs Research, Nanchang, 330022, China.
| | - Tao Yuan
- School of Health, Jiangxi Normal University, Jiangxi Province Key Laboratory of Natural and Biomimetic Drugs Research, Nanchang, 330022, China; College of Life Science, Jiangxi Normal University, Nanchang, 330022, China.
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18
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Das SC, Tasnim W, Rana HK, Acharjee UK, Islam MM, Khatun R. Comprehensive bioinformatics and machine learning analyses for breast cancer staging using TCGA dataset. Brief Bioinform 2024; 26:bbae628. [PMID: 39656775 DOI: 10.1093/bib/bbae628] [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: 07/15/2024] [Revised: 10/23/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024] Open
Abstract
Breast cancer is an alarming global health concern, including a vast and varied set of illnesses with different molecular characteristics. The fusion of sophisticated computational methodologies with extensive biological datasets has emerged as an effective strategy for unravelling complex patterns in cancer oncology. This research delves into breast cancer staging, classification, and diagnosis by leveraging the comprehensive dataset provided by the The Cancer Genome Atlas (TCGA). By integrating advanced machine learning algorithms with bioinformatics analysis, it introduces a cutting-edge methodology for identifying complex molecular signatures associated with different subtypes and stages of breast cancer. This study utilizes TCGA gene expression data to detect and categorize breast cancer through the application of machine learning and systems biology techniques. Researchers identified differentially expressed genes in breast cancer and analyzed them using signaling pathways, protein-protein interactions, and regulatory networks to uncover potential therapeutic targets. The study also highlights the roles of specific proteins (MYH2, MYL1, MYL2, MYH7) and microRNAs (such as hsa-let-7d-5p) that are the potential biomarkers in cancer progression founded on several analyses. In terms of diagnostic accuracy for cancer staging, the random forest method achieved 97.19%, while the XGBoost algorithm attained 95.23%. Bioinformatics and machine learning meet in this study to find potential biomarkers that influence the progression of breast cancer. The combination of sophisticated analytical methods and extensive genomic datasets presents a promising path for expanding our understanding and enhancing clinical outcomes in identifying and categorizing this intricate illness.
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Affiliation(s)
- Saurav Chandra Das
- Department of Computer Science and Engineering, Jagannath University, Dhaka-1100, Bangladesh
- Department of Internet of Things and Robotics Engineering, Bangabandhu Sheikh Mujibur Rahman Digital University, Bangladesh, Kaliakair, Gazipur-1750, Bangladesh
| | - Wahia Tasnim
- Department of Computer Science and Engineering, Green University of Bangladesh, Narayanganj-1461, Dhaka, Bangladesh
| | - Humayan Kabir Rana
- Department of Computer Science and Engineering, Green University of Bangladesh, Narayanganj-1461, Dhaka, Bangladesh
| | - Uzzal Kumar Acharjee
- Department of Computer Science and Engineering, Jagannath University, Dhaka-1100, Bangladesh
| | - Md Manowarul Islam
- Department of Computer Science and Engineering, Jagannath University, Dhaka-1100, Bangladesh
| | - Rabea Khatun
- Department of Computer Science and Engineering, Green University of Bangladesh, Narayanganj-1461, Dhaka, Bangladesh
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19
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Chutoe C, Inson I, Krobthong S, Phueakphud N, Khunluck T, Wongtrakoongate P, Charoenphandhu N, Lertsuwan K. Combinatorial effects of cannabinoid receptor 1 and 2 agonists on characteristics and proteomic alteration in MDA-MB-231 breast cancer cells. PLoS One 2024; 19:e0312851. [PMID: 39527598 PMCID: PMC11554208 DOI: 10.1371/journal.pone.0312851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Breast cancer is the most common cancer diagnosed in women worldwide. However, the effective treatment for breast cancer progression is still being sought. The activation of cannabinoid receptor (CB) has been shown to negatively affect breast cancer cell survival. Our previous study also reported that breast cancer cells responded to various combinations of CB1 and CB2 agonists differently. Nonetheless, the mechanism underlying this effect and whether this phenomenon can be seen in other cancer characteristics remain unknown. Therefore, this study aims to further elucidate the effects of highly selective CB agonists and their combination on triple-negative breast cancer proliferation, cell cycle progression, invasion, lamellipodia formation as well as proteomic profile of MDA-MB-231 breast cancer cells. The presence of CB agonists, specifically a 2:1 (ACEA: GW405833) combination, prominently inhibited colony formation and induced the S-phase cell cycle arrest in MDA-MB-231 cells. Furthermore, cell invasion ability and lamellipodia formation of MDA-MB-231 were also attenuated by the exposure of CB agonists and their 2:1 combination ratio. Our proteomic analysis revealed proteomic profile alteration in MDA-MB-231 upon CB exposure that potentially led to breast cancer suppression, such as ZPR1/SHC1/MAPK-mediated cell proliferation and AXL/VAV2/RAC1-mediated cell motility pathways. Our findings showed that selective CB agonists and their combination suppressed breast cancer characteristics in MDA-MB-231 cells. The exposure of CB agonists also altered the proteomic profile of MDA-MB-231, which could lead to cell proliferation and motility suppression.
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Affiliation(s)
- Chartinun Chutoe
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Ingon Inson
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Sucheewin Krobthong
- Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Nut Phueakphud
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
- Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tueanjai Khunluck
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Patompon Wongtrakoongate
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
- Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Narattaphol Charoenphandhu
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
- The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
| | - Kornkamon Lertsuwan
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
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20
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Zhao W, Wang W, Zhu Y, Lv Z, Xu W. Molecular mechanisms and clinicopathological characteristics of inhibin βA in thyroid cancer metastasis. Int J Mol Med 2024; 54:99. [PMID: 39301627 DOI: 10.3892/ijmm.2024.5423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/14/2024] [Indexed: 09/22/2024] Open
Abstract
The present study aimed to investigate the role and mechanism of inhibin βA (INHBA) in thyroid cancer (TC), and to determine its potential impact on the aggressive behavior of TC cells. The present study employed a comprehensive approach, using public databases, such as the Gene Expression Omnibus and The Cancer Genome Atlas, to identify and analyze the expression of INHBA in TC. Cell transfection, reverse transcription‑quantitative PCR, western blot analysis, immunohistochemistry and in vivo assays were conducted to investigate the functional effects of INHBA on TC. In addition, the present study explored the molecular mechanisms underlying the effects of INHBA, focusing on the potential impact on the RhoA signaling pathway and associated molecular cascades. Bioinformatics analysis revealed a significant association between INHBA expression and TC, and INHBA expression was markedly upregulated in TC tissues compared with in healthy control tissues. The results of functional studies demonstrated that INHBA overexpression increased the migration and invasion of TC cells, and the opposite result was observed following INHBA knockdown. Mechanistic investigations indicated that INHBA modulated the RhoA pathway, leading to alterations in the phosphorylation status of LIM kinase 1 (LIMK) and cofilin, key regulators of cytoskeletal dynamics and cell motility. Following the introduction of transfected TC cells into zebrafish and nude mouse models, the results of the present study demonstrated that INHBA knockdown attenuated the metastatic potential of TC cells. In conclusion, INHBA may serve a pivotal role in promoting the aggressive phenotype of TC cells through modulating the RhoA/LIMK/cofilin signaling axis. These findings highlight INHBA as a potential biomarker and therapeutic target for the management of aggressive TC.
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Affiliation(s)
- Wanjun Zhao
- Department of Otolaryngology‑Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Weiyu Wang
- Department of Otolaryngology‑Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Yifan Zhu
- Department of Otolaryngology‑Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Zhenghua Lv
- Department of Otolaryngology‑Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Wei Xu
- Department of Otolaryngology‑Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250022, P.R. China
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21
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Tashakori N, Mikhailova MV, Mohammedali ZA, Mahdi MS, Ali Al-Nuaimi AM, Radi UK, Alfaraj AM, Kiasari BA. Circular RNAs as a novel molecular mechanism in diagnosis, prognosis, therapeutic target, and inhibiting chemoresistance in breast cancer. Pathol Res Pract 2024; 263:155569. [PMID: 39236498 DOI: 10.1016/j.prp.2024.155569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
Breast cancer (BC) is the most common cancer among women, characterized by significant heterogeneity. Diagnosis of the disease in the early stages and appropriate treatment plays a crucial role for these patients. Despite the available treatments, many patients due to drug resistance do not receive proper treatments. Recently, circular RNAs (circRNAs), a type of non-coding RNAs (ncRNAs), have been discovered to be involved in the progression and resistance to drugs in BC. CircRNAs can promote or inhibit malignant cells by their function. Numerous circRNAs have been discovered to be involved in the proliferation, invasion, and migration of tumor cells, as well as the progression, pathogenesis, tumor metastasis, and drug resistance of BC. Circular RNAs can also serve as a biomarker for diagnosing, predicting prognosis, and targeting therapy. In this review, we present an outline of the variations in circRNAs expression in various BCs, the functional pathways, their impact on the condition, and their uses in clinical applications.
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Affiliation(s)
- Nafiseh Tashakori
- Department of Medicine, Faculty of Internal Medicine,Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Maria V Mikhailova
- Department of Prosthetic Dentistry, I.M. Schenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | | | | | - Usama Kadem Radi
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq
| | | | - Bahman Abedi Kiasari
- Microbiology & Immunology Group, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
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22
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Huang L, Wang J, Wang X, Zheng S, Liang K, Kang YE, Chang JW, Koo BS, Liu L, Gal A, Shan Y. Sulforaphane suppresses bladder cancer metastasis via blocking actin nucleation-mediated pseudopodia formation. Cancer Lett 2024; 601:217145. [PMID: 39084455 DOI: 10.1016/j.canlet.2024.217145] [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: 07/14/2023] [Revised: 06/14/2024] [Accepted: 07/28/2024] [Indexed: 08/02/2024]
Abstract
Metastasis is the primary stumbling block to the treatment of bladder cancer (BC). In order to spread, tumor cells must acquire increased migratory and invasive capacity, which is tightly linked with pseudopodia formation. Here, we unravel the effects of sulforaphane (SFN), an isothiocyanate in cruciferous vegetables, on the assembly of pseudopodia and BC metastasis, and its molecular mechanism in the process. Our database analysis revealed that in bladder tumor, pseudopodia-associated genes, CTTN, WASL and ACTR2/ARP2 are upregulated. SFN caused lamellipodia to collapse in BC cells by blocking the CTTN-ARP2 axis. SFN inhibited invadopodia formation and cell invasion by reducing WASL in different invasive BC cell lines. The production of ATP, essential for the assembly of pseudopodia, was significantly increased in bladder tumors and strongly inhibited by SFN. Overexpressing AKT1 reversed the downregulation of ATP in SFN-treated bladder cancer cells and restored filopodia and lamellipodia morphology and function. Bioluminescent imaging showed that SFN suppressed BC metastases to the lung of nude mice while downregulating Cttn and Arp2 expression. Our study thus reveals mechanisms of SFN action in inhibiting pseudopodia formation and highlights potential targeting options for the therapy of metastatic bladder cancer.
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Affiliation(s)
- Lei Huang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, 999077, Hong Kong Special Administrative Region
| | - Jiaxin Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xinyi Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China
| | - Sicong Zheng
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China
| | - Kailin Liang
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yea Eun Kang
- Department of Internal Medicine, School of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Jae Won Chang
- Department of Otolaryngology-Head and Neck Surgery, Chungnam National University, College of Medicine, Daejeon, 35015, Republic of Korea
| | - Bon Seok Koo
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, 35015, Republic of Korea
| | - Lihua Liu
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China.
| | - Annamaria Gal
- School of Applied Sciences, University of Brighton, Brighton, BN2 4GJ, United Kingdom.
| | - Yujuan Shan
- School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China; Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou, 325035, China.
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23
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Pelaz SG, Flores-Hernández R, Vujic T, Schvartz D, Álvarez-Vázquez A, Ding Y, García-Vicente L, Belloso A, Talaverón R, Sánchez JC, Tabernero A. A proteomic approach supports the clinical relevance of TAT-Cx43 266-283 in glioblastoma. Transl Res 2024; 272:95-110. [PMID: 38876188 DOI: 10.1016/j.trsl.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/18/2024] [Accepted: 06/01/2024] [Indexed: 06/16/2024]
Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary brain cancer. The Src inhibitor, TAT-Cx43266-283, exerts antitumor effects in in vitro and in vivo models of GBM. Because addressing the mechanism of action is essential to translate these results to a clinical setting, in this study we carried out an unbiased proteomic approach. Data-independent acquisition mass spectrometry proteomics allowed the identification of 190 proteins whose abundance was modified by TAT-Cx43266-283. Our results were consistent with the inhibition of Src as the mechanism of action of TAT-Cx43266-283 and unveiled antitumor effectors, such as p120 catenin. Changes in the abundance of several proteins suggested that TAT-Cx43266-283 may also impact the brain microenvironment. Importantly, the proteins whose abundance was reduced by TAT-Cx43266-283 correlated with an improved GBM patient survival in clinical datasets and none of the proteins whose abundance was increased by TAT-Cx43266-283 correlated with shorter survival, supporting its use in clinical trials.
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Affiliation(s)
- Sara G Pelaz
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
| | - Raquel Flores-Hernández
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Tatjana Vujic
- Department of Medicine, University of Geneva, 1211, Geneva, Switzerland; University Center of Legal Medicine, Lausanne-Geneva, Lausanne University Hospital and University of Lausanne, Geneva University Hospital and University of Geneva, Lausanne Geneva, Switzerland
| | - Domitille Schvartz
- Department of Medicine, University of Geneva, 1211, Geneva, Switzerland; University of Geneva, Faculty of Medicine, Proteomics Core Facility, Geneva, Switzerland
| | - Andrea Álvarez-Vázquez
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Yuxin Ding
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Laura García-Vicente
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Aitana Belloso
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Rocío Talaverón
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | | | - Arantxa Tabernero
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
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24
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Pracharova J, Cyrikova T, Berecka M, Biersack B, Kasparkova J, Brabec V. Antimetastatic activity of (arene)ruthenium(II) complex of 4-aryl-4H-naphthopyran. Chem Biol Interact 2024; 400:111180. [PMID: 39089413 DOI: 10.1016/j.cbi.2024.111180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/21/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024]
Abstract
Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.
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Affiliation(s)
- Jitka Pracharova
- Department of Biophysics, Faculty of Science, Palacky University, CZ-77900, Olomouc, Czech Republic
| | - Tereza Cyrikova
- Department of Biophysics, Faculty of Science, Palacky University, CZ-77900, Olomouc, Czech Republic
| | - Michal Berecka
- Department of Biophysics, Faculty of Science, Palacky University, CZ-77900, Olomouc, Czech Republic
| | - Bernhard Biersack
- Organic Chemistry Laboratory, University Bayreuth, 95440, Bayreuth, Germany
| | - Jana Kasparkova
- Department of Biophysics, Faculty of Science, Palacky University, CZ-77900, Olomouc, Czech Republic; Czech Academy of Sciences, Institute of Biophysics, CZ-61200, Brno, Czech Republic
| | - Viktor Brabec
- Department of Biophysics, Faculty of Science, Palacky University, CZ-77900, Olomouc, Czech Republic; Czech Academy of Sciences, Institute of Biophysics, CZ-61200, Brno, Czech Republic.
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25
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Parihar K, Ko SHB, Bradley RP, Taylor P, Ramakrishnan N, Baumgart T, Guo W, Weaver VM, Janmey PA, Radhakrishnan R. Asymmetric crowders and membrane morphology at the nexus of intracellular trafficking and oncology. MECHANOBIOLOGY IN MEDICINE 2024; 2:100071. [PMID: 38899029 PMCID: PMC11185830 DOI: 10.1016/j.mbm.2024.100071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
A definitive understanding of the interplay between protein binding/migration and membrane curvature evolution is emerging but needs further study. The mechanisms defining such phenomena are critical to intracellular transport and trafficking of proteins. Among trafficking modalities, exosomes have drawn attention in cancer research as these nano-sized naturally occurring vehicles are implicated in intercellular communication in the tumor microenvironment, suppressing anti-tumor immunity and preparing the metastatic niche for progression. A significant question in the field is how the release and composition of tumor exosomes are regulated. In this perspective article, we explore how physical factors such as geometry and tissue mechanics regulate cell cortical tension to influence exosome production by co-opting the biophysics as well as the signaling dynamics of intracellular trafficking pathways and how these exosomes contribute to the suppression of anti-tumor immunity and promote metastasis. We describe a multiscale modeling approach whose impact goes beyond the fundamental investigation of specific cellular processes toward actual clinical translation. Exosomal mechanisms are critical to developing and approving liquid biopsy technologies, poised to transform future non-invasive, longitudinal profiling of evolving tumors and resistance to cancer therapies to bring us one step closer to the promise of personalized medicine.
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Affiliation(s)
- Kshitiz Parihar
- Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - Seung-Hyun B. Ko
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - Ryan P. Bradley
- Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - Phillip Taylor
- Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - N. Ramakrishnan
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
| | - Tobias Baumgart
- Department of Chemistry, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Valerie M. Weaver
- Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA, USA
| | - Paul A. Janmey
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ravi Radhakrishnan
- Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA
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26
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Kuang J, Liu H, Feng L, Xue Y, Tang H, Xu P. How mitochondrial dynamics imbalance affects the progression of breast cancer:a mini review. Med Oncol 2024; 41:238. [PMID: 39218840 PMCID: PMC11366726 DOI: 10.1007/s12032-024-02479-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2024] [Indexed: 09/04/2024]
Abstract
Despite the high incidence of breast cancer in women worldwide, there are still great challenges in the treatment process. Mitochondria are highly dynamic organelles, and their dynamics involve cellular energy conversion, signal conduction and other processes. In recent years, an increasing number of studies have affirmed the dynamics of mitochondria as the basis for cancer progression and metastasis; that is, an imbalance between mitochondrial fission and fusion may lead to the progression and metastasis of breast cancer. Here, we review the latest insights into mitochondrial dynamics in the progression of breast cancer and emphasize the clinical value of mitochondrial dynamics in diagnosis and prognosis, as well as important advances in clinical research.
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Affiliation(s)
- Jingwen Kuang
- The 1st Affiliated Hospital of He'nan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Hao Liu
- He'nan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Linlin Feng
- The 1st Affiliated Hospital of He'nan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Yuan Xue
- The 1st Affiliated Hospital of He'nan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Huiyi Tang
- Department of Sports Medicine, Guangzhou Sport University, Guangzhou, Guangdong, People's Republic of China.
| | - Pengcheng Xu
- The 1st Affiliated Hospital of He'nan University of Science and Technology, Luoyang, Henan, People's Republic of China.
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27
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Nakka P, Jassi C, Chen MC, Liu YS, Liu JY, Yeh CM, Li CC, Chang YC, Kuo WW, Huang CY. Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1. Cancer Cell Int 2024; 24:291. [PMID: 39152428 PMCID: PMC11328471 DOI: 10.1186/s12935-024-03450-x] [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: 06/11/2023] [Accepted: 07/13/2024] [Indexed: 08/19/2024] Open
Abstract
BACKGROUND Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. METHODS MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. RESULTS Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. CONCLUSION Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.
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Affiliation(s)
- Parvathi Nakka
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan
| | - Chikondi Jassi
- Department of Biological Science and Technology, China Medical University, Taichung, 406, Taiwan
| | - Ming-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Sheng Liu
- Division of Hematology and Oncology, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Jer-Yuh Liu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chung-Min Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, 500, Taiwan
| | - Chi-Cheng Li
- School of Medicine, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yu-Chun Chang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung, 406, Taiwan
- Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, 406, Taiwan
| | - Chih-Yang Huang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan.
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan.
- Department of Biotechnology, Asia University, Taichung, 413, Taiwan.
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Wang F, Xie L, Tang Y, Deng T. Unraveling Crucial Mitochondria-Related Genes in the Transition from Ulcerative Colitis to Colorectal Cancer. Drug Des Devel Ther 2024; 18:3175-3189. [PMID: 39071816 PMCID: PMC11283795 DOI: 10.2147/dddt.s455098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 07/17/2024] [Indexed: 07/30/2024] Open
Abstract
Purpose To clarify the significance of mitochondria-related differentially expressed genes (MTDEGs) in UC carcinogenesis through a bioinformatics analysis and provide potential therapeutic targets for patients with UC associated colorectal cancer. Methods Microarray GSE37283 was utilized to investigate differentially expressed genes (DEGs) in UC and UC with neoplasia (UCN). MTDEGs were identified by intersecting DEGs with human mitochondrial genes. Utilizing LASSO and random forest analyses, we identified three crucial genes. Subsequently, using ROC curve to investigate the predictive ability of three key genes. Following, three key genes were confirmed in AOM/DSS mice model by Real-time PCR. Finally, single-sample gene set enrichment analysis (ssGSEA) was employed to explore the correlation between the hub genes and immune cells infiltration in UC carcinogenesis. Results The three identified hub MTDEGs (HMGCS2, MAVS, RDH13) may exhibit significant diagnostic specificity in the transition from UC to UCN. Real-time PCR assay further confirmed that the expressions of HMGCS2 and RDH13 were significantly downregulated in UCN mice than that in UC mice. ssGSEA analysis revealed the hub genes were highly associated with CD56dim natural killer cells. Conclusion RDH13, HMGCS2, and MAVS may become diagnostic indicators and potential biomarkers for UCN. Our research has the potential to enhance our understanding of the mechanisms underlying carcinogenesis in UC.
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Affiliation(s)
- Fanqi Wang
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China
| | - Limin Xie
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China
| | - Yuan Tang
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of China
- Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China
| | - Tuo Deng
- Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China
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Patterson MR, Cogan JA, Cassidy R, Theobald DA, Wang M, Scarth JA, Anene CA, Whitehouse A, Morgan EL, Macdonald A. The Hippo pathway transcription factors YAP and TAZ play HPV-type dependent roles in cervical cancer. Nat Commun 2024; 15:5809. [PMID: 38987584 PMCID: PMC11237029 DOI: 10.1038/s41467-024-49965-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 06/21/2024] [Indexed: 07/12/2024] Open
Abstract
Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers.
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Affiliation(s)
- Molly R Patterson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
| | - Joseph A Cogan
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
| | - Rosa Cassidy
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
| | - Daisy A Theobald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
| | - Miao Wang
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
| | - James A Scarth
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Chinedu A Anene
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Biomedical Science Research, Leeds Beckett University, Leeds, UK
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
| | - Ethan L Morgan
- School of Life Sciences, University of Sussex, Brighton, UK
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
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Nitsch A, Marthaler P, Qarqash S, Bemmann M, Bekeschus S, Wassilew GI, Haralambiev L. Cold Physical Plasma Reduces Motility of Various Bone Sarcoma Cells While Remodeling the Cytoskeleton. In Vivo 2024; 38:1571-1578. [PMID: 38936915 PMCID: PMC11215588 DOI: 10.21873/invivo.13607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/25/2024] [Accepted: 04/08/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND/AIM Cold physical plasma (CPP) has emerged as an effective therapy in oncology by inducing cytotoxic effects in various cancer cells, including chondrosarcoma (CS), Ewing's sarcoma (ES), and osteosarcoma (OS). The current study investigated the impact of CPP on cell motility in CS (CAL-78), ES (A673), and OS (U2-OS) cell lines, focusing on the actin cytoskeleton. MATERIALS AND METHODS The CASY Cell Counter and Analyzer was used to study cell proliferation and determine the optimal concentrations of fetal calf serum to maintain viability without stimulation of cell proliferation. CellTiter-BlueCell viability assay was used to determine the effects of CPP on the viability of bone sarcoma cells. The Radius assay was used to determine cell migration. Staining for Deoxyribonuclease I, G-actin, and F-actin was used to assay for the effects on the cytoskeleton. RESULTS Reductions in cell viability and motility were observed across all cell lines following CPP treatment. CPP induced changes in the actin cytoskeleton, leading to decreased cell motility. CONCLUSION CPP effectively reduces the motility of bone sarcoma cells by altering the actin cytoskeleton. These findings underscore CPP's potential as a therapeutic tool for bone sarcomas and highlight the need for further research in this area.
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Affiliation(s)
- Andreas Nitsch
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany;
| | - Pauline Marthaler
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Sara Qarqash
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Maximilian Bemmann
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Sander Bekeschus
- ZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Greifswald, Germany
- Clinic and Policlinic for Dermatology and Venerology, Rostock University Medical Center, Rostock, Germany
| | - Georgi I Wassilew
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Lyubomir Haralambiev
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany
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Tan EW, Abdullah ADI, Ming LC, Poh CL, Goh BH, Lau TP, Tan KO. Adenovirus-mediated expression of MOAP-1, Bax and RASSF1A antagonizes chemo-drug resistance of human breast cancer cells expressing cancer stem cell markers. Biomed Pharmacother 2024; 176:116744. [PMID: 38810399 DOI: 10.1016/j.biopha.2024.116744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/31/2024] Open
Abstract
Cancer is one of the major leading causes of mortality globally and chemo-drug-resistant cancers pose significant challenges to cancer treatment by reducing patient survival rates and increasing treatment costs. Although the mechanisms of chemoresistance vary among different types of cancer, cancer cells are known to share several hallmarks, such as their resistance to apoptosis as well as the ability of cancer stem cells to produce metastatic daughter cells that are resistant to chemotherapy. To address the issue of chemo-drug resistance in cancer cells, a tetracistronic expression construct, Ad-MBR-GFP, encoding adenovirus-mediated expression of MOAP-1, Bax, RASSSF1A, and GFP, was generated to investigate its potential activity in reducing or inhibiting the chemo-drug resistant activity of the human breast cancer cells, MCF-7-CR and MDA-MB-231. When infected by Ad-MBR-GFP, the cancer cells exhibited round cell morphology and nuclei condensation with positive staining for annexin-V. Furthermore, our results showed that both MCF-7-CR and MDA-MB-231 cells stained positively for CD 44 and negatively for CD 24 (CD44+/CD24-) with high levels of endogenous ALDH activity whereas SNU-1581 breast cancer cells were identified as CD 44-/CD 24- cells with relatively low levels of endogenous ALDH activity and high sensitivity toward chemo-drugs, suggesting that both CD 44 and ALDH activity contribute to chemo-drug resistance. Moreover, both MCF-7-CR and MDA-MB-231 cells showed strong chemo-drug sensitivity to cisplatin when the cells were infected by Ad-MBR-GFP, leading to 9-fold and 2-fold reduction in the IC 50 values when compared to cisplatin treatment alone, respectively. The data were further supported by 3D (soft agar) and spheroid cell models of MCF-7-CR and MDA-MB-231 cells which showed a 2-fold reduction of a number of cell colonies and spheroid size when treated with both Ad-MBR-GFP and cisplatin, and compared to control. Other than chemo-sensitivity, Ad-MBR-GFP-infected cancer cells retarded cell migration. Flow cytometry analysis showed that the mechanism of action of Ad-MBR-GFP involved cell cycle arrest at the G1 phase and inhibition of cellular DNA synthesis. Taken together, our investigation showed that Ad-MBR-GFP mediated chemo-drug sensitization in the infected cancer cells involved the activation of apoptosis signaling, cell cycle arrest, and inhibition of DNA synthesis, suggesting that Ad-MBR-GFP is potentially efficacious for the treatment of chemo-drug resistant cancers.
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Affiliation(s)
- Ee Wern Tan
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia; Sunway Biofunctional Molecules Discovery Centre, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
| | - Amar Daud Iskandar Abdullah
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
| | - Long Chiau Ming
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
| | - Bey Hing Goh
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia; Sunway Biofunctional Molecules Discovery Centre, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo 2007, NSW, Australia
| | - Tze Pheng Lau
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia.
| | - Kuan Onn Tan
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia.
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He L, Ioannidis A, Hoffman CJ, Arambula E, Joshi P, Whitelegge J, Liau LM, Kornblum HI, Pajonk F. Activation of the Mevalonate Pathway in Response to Anti-cancer Treatments Drives Glioblastoma Recurrences Through Activation of Rac-1. CANCER RESEARCH COMMUNICATIONS 2024; 4:1566-1580. [PMID: 38837899 PMCID: PMC11197925 DOI: 10.1158/2767-9764.crc-24-0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/26/2024] [Accepted: 05/31/2024] [Indexed: 06/07/2024]
Abstract
Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation. SIGNIFICANCE Combination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.
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Affiliation(s)
- Ling He
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
| | - Angeliki Ioannidis
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Carter J. Hoffman
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Evelyn Arambula
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Purva Joshi
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Julian Whitelegge
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Psychiatry and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Linda M. Liau
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Harley I. Kornblum
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Psychiatry and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
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Liu W, Wang X, Yu H, Yan G, Shen S, Gao M, Zhang X. Integrated Platform for Large-Scale Quantitative Profiling of Phosphotyrosine Signaling Complexes Based on Cofractionation/Mass Spectrometry and Complex-Centric Algorithm. Anal Chem 2024; 96:9849-9858. [PMID: 38836774 DOI: 10.1021/acs.analchem.4c00285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
The scarcity and dynamic nature of phosphotyrosine (pTyr)-modified proteins pose a challenge for researching protein complexes with pTyr modification, which are assembled through multiple protein-protein interactions. We developed an integrated complex-centric platform for large-scale quantitative profiling of pTyr signaling complexes based on cofractionation/mass spectrometry (CoFrac-MS) and a complex-centric algorithm. We initially constructed a trifunctional probe based on pTyr superbinder (SH2-S) for specifically binding and isolation of intact pTyr protein complexes. Then, the CoFrac-MS strategy was employed for the identification of pTyr protein complexes by integrating ion exchange chromatography in conjunction with data independent acquisition mass spectrometry. Furthermore, we developed a novel complex-centric algorithm for quantifying protein complexes based on the protein complex elution curve. Utilizing this algorithm, we effectively quantified 216 putative protein complexes. We further screened 21 regulated pTyr protein complexes related to the epidermal growth factor signal. Our study engenders a comprehensive framework for the intricate examination of pTyr protein complexes and presents, for the foremost occasion, a quantitative landscape delineating the composition of pTyr protein complexes in HeLa cells.
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Affiliation(s)
- Wei Liu
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Xuantang Wang
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Hailong Yu
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Guoquan Yan
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Shun Shen
- Pharmacy Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Mingxia Gao
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
- Pharmacy Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Xiangmin Zhang
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
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Mottareale R, Frascogna C, La Verde G, Arrichiello C, Muto P, Netti PA, Fusco S, Panzetta V, Pugliese M. Impact of ionizing radiation on cell-ECM mechanical crosstalk in breast cancer. Front Bioeng Biotechnol 2024; 12:1408789. [PMID: 38903185 PMCID: PMC11187264 DOI: 10.3389/fbioe.2024.1408789] [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: 03/28/2024] [Accepted: 05/16/2024] [Indexed: 06/22/2024] Open
Abstract
The stiffness of the extracellular matrix plays a crucial role in cell motility and spreading, influencing cell morphology through cytoskeleton organization and transmembrane proteins' expression. In this context, mechanical characterization of both cells and the extracellular matrix gains prominence for enhanced diagnostics and clinical decision-making. Here, we investigate the combined effect of mechanotransduction and ionizing radiations on altering cells' mechanical properties, analysing mammary cell lines (MCF10A and MDA-MB-231) after X-ray radiotherapy (2 and 10 Gy). We found that ionizing radiations sensitively affect adenocarcinoma cells cultured on substrates mimicking cancerous tissue stiffness (15 kPa), inducing an increased structuration of paxillin-rich focal adhesions and cytoskeleton: this process translates in the augmentation of tension at the actin filaments level, causing cellular stiffness and consequently affecting cytoplasmatic/nuclear morphologies. Deeper exploration of the intricate interplay between mechanical factors and radiation should provide novel strategies to orient clinical outcomes.
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Affiliation(s)
- Rocco Mottareale
- Department of Physics “E. Pancini”, University of Naples Federico II, Naples, Italy
- Institute of Applied Sciences and Intelligent Systems E. Caianiello (CNR-ISASI), Pozzuoli, Italy
| | - Crescenzo Frascogna
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy
| | - Giuseppe La Verde
- Department of Physics “E. Pancini”, University of Naples Federico II, Naples, Italy
| | - Cecilia Arrichiello
- Radiotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione “G. Pascale”, Naples, Italy
| | - Paolo Muto
- Radiotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione “G. Pascale”, Naples, Italy
| | - Paolo A. Netti
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy
- Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Naples, Italy
| | - Sabato Fusco
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Naples, Italy
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
| | - Valeria Panzetta
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy
- Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Naples, Italy
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Sun F, Fang M, Zhang H, Song Q, Li S, Li Y, Jiang S, Yang L. Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway. Cell Biochem Biophys 2024; 82:435-455. [PMID: 38438751 DOI: 10.1007/s12013-024-01245-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2024] [Indexed: 03/06/2024]
Abstract
Drp1 (Dynamin-Related Protein 1) is a cytoplasmic GTPase protein encoded by the DNM1L gene that influences mitochondrial dynamics by mediating mitochondrial fission processes. Drp1 has been demonstrated to play an important role in a variety of life activities such as cell survival, proliferation, migration, and death. Drp1 has been shown to play different physiological roles under different physiological conditions, such as normal and inflammation. Recently studies have revealed that Drp1 plays a critical role in the occurrence, development, and aggravation of a series of diseases, thereby it serves as a potential therapeutic target for them. In this paper, we review the structure and biological properties of Drp1, summarize the biological processes that occur in the inflammatory response to Drp1, discuss its role in various cancers triggered by the mitochondrial pathway and investigate effective methods for targeting Drp1 in cancer treatment. We also synthesized the phenomena of Drp1 involving in the triggering of other diseases. The results discussed herein contribute to our deeper understanding of mitochondrial kinetic pathway-induced diseases and their therapeutic applications. It is critical for advancing the understanding of the mechanisms of Drp1-induced mitochondrial diseases and preventive therapies.
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Affiliation(s)
- Fulin Sun
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
- Health Science Center, Qingdao University, Qingdao, China
| | - Min Fang
- Department of Gynaecology, Qingdao Women and Children's Hospital, Qingdao, 266021, Shandong, China
| | - Huhu Zhang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Qinghang Song
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
- Health Science Center, Qingdao University, Qingdao, China
| | - Shuang Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Ya Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Shuyao Jiang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
- Health Science Center, Qingdao University, Qingdao, China
| | - Lina Yang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China.
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Pratiwi L, Elisa E, Sutanto H. Probing the protrusions: lamellipodia and filopodia in cancer invasion and beyond. MECHANOBIOLOGY IN MEDICINE 2024; 2:100064. [PMID: 40395858 PMCID: PMC12082305 DOI: 10.1016/j.mbm.2024.100064] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 05/22/2025]
Abstract
The dynamic protrusions of lamellipodia and filopodia have emerged as crucial players in tumor progression and metastasis. These membrane structures, governed by intricate actin cytoskeletal rearrangements, facilitate cancer cell migration, invasion, and interaction with the tumor microenvironment. This review provides a comprehensive examination of the structural and functional attributes of lamellipodia and filopodia, shedding light on their pivotal roles in mediating cancer invasion. Navigating through the intricate landscape of cancer biology, the review illuminates the intricate signaling pathways and regulatory mechanisms orchestrating the formation and activity of these protrusions. The discussion extends to the clinical implications of lamellipodia and filopodia, exploring their potential as diagnostic and prognostic markers, and delving into therapeutic strategies that target these structures to impede cancer progression. As we delve into the future, the review outlines emerging technologies and unexplored facets that beckon further research, emphasizing the need for collaborative efforts to unravel the complexities of lamellipodia and filopodia in cancer, ultimately paving the way for innovative therapeutic interventions.
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Affiliation(s)
- Laras Pratiwi
- Internal Medicine Residency Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Elisa Elisa
- Internal Medicine Residency Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Henry Sutanto
- Internal Medicine Residency Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
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Goldstein Y, Cohen OT, Wald O, Bavli D, Kaplan T, Benny O. Particle uptake in cancer cells can predict malignancy and drug resistance using machine learning. SCIENCE ADVANCES 2024; 10:eadj4370. [PMID: 38809990 PMCID: PMC11314625 DOI: 10.1126/sciadv.adj4370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 04/23/2024] [Indexed: 05/31/2024]
Abstract
Tumor heterogeneity is a primary factor that contributes to treatment failure. Predictive tools, capable of classifying cancer cells based on their functions, may substantially enhance therapy and extend patient life span. The connection between cell biomechanics and cancer cell functions is used here to classify cells through mechanical measurements, via particle uptake. Machine learning (ML) was used to classify cells based on single-cell patterns of uptake of particles with diverse sizes. Three pairs of human cancer cell subpopulations, varied in their level of drug resistance or malignancy, were studied. Cells were allowed to interact with fluorescently labeled polystyrene particles ranging in size from 0.04 to 3.36 μm and analyzed for their uptake patterns using flow cytometry. ML algorithms accurately classified cancer cell subtypes with accuracy rates exceeding 95%. The uptake data were especially advantageous for morphologically similar cell subpopulations. Moreover, the uptake data were found to serve as a form of "normalization" that could reduce variation in repeated experiments.
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Affiliation(s)
- Yoel Goldstein
- Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Ora T. Cohen
- Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Ori Wald
- Department of Cardiothoracic Surgery, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Danny Bavli
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Tommy Kaplan
- School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
- Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Ofra Benny
- Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
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38
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Hohmann M, Brunner V, Johannes W, Schum D, Carroll LM, Liu T, Sasaki D, Bosch J, Clavel T, Sieber SA, Zeller G, Tschurtschenthaler M, Janßen KP, Gulder TAM. Bacillamide D produced by Bacillus cereus from the mouse intestinal bacterial collection (miBC) is a potent cytotoxin in vitro. Commun Biol 2024; 7:655. [PMID: 38806706 PMCID: PMC11133360 DOI: 10.1038/s42003-024-06208-3] [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: 12/10/2023] [Accepted: 04/17/2024] [Indexed: 05/30/2024] Open
Abstract
The gut microbiota influences human health and the development of chronic diseases. However, our understanding of potentially protective or harmful microbe-host interactions at the molecular level is still in its infancy. To gain further insights into the hidden gut metabolome and its impact, we identified a cryptic non-ribosomal peptide BGC in the genome of Bacillus cereus DSM 28590 from the mouse intestine ( www.dsmz.de/miBC ), which was predicted to encode a thiazol(in)e substructure. Cloning and heterologous expression of this BGC revealed that it produces bacillamide D. In-depth functional evaluation showed potent cytotoxicity and inhibition of cell migration using the human cell lines HCT116 and HEK293, which was validated using primary mouse organoids. This work establishes the bacillamides as selective cytotoxins from a bacterial gut isolate that affect mammalian cells. Our targeted structure-function-predictive approach is demonstrated to be a streamlined method to discover deleterious gut microbial metabolites with potential effects on human health.
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Affiliation(s)
- Maximilian Hohmann
- Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany
| | - Valentina Brunner
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
- Division of Translational Cancer Research German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
| | - Widya Johannes
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
| | - Dominik Schum
- Department of Bioscience, Center for Functional Protein Assemblies, Technical University of Munich, 85748, Garching bei München, Germany
| | - Laura M Carroll
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, 61997, Heidelberg, Germany
| | - Tianzhe Liu
- Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany
| | - Daisuke Sasaki
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
- Research and Development Headquarters, Nitto Boseki Co., Ltd., 102-8489, Tokyo, Japan
| | - Johanna Bosch
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, 52074, Aachen, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, 52074, Aachen, Germany
| | - Stephan A Sieber
- Department of Bioscience, Center for Functional Protein Assemblies, Technical University of Munich, 85748, Garching bei München, Germany
| | - Georg Zeller
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, 61997, Heidelberg, Germany
| | - Markus Tschurtschenthaler
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany.
- Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany.
- Division of Translational Cancer Research German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
| | - Klaus-Peter Janßen
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany.
| | - Tobias A M Gulder
- Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany.
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Natural Product Biotechnology, Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy at Saarland University, Campus E8.1, 66123, Saarbrücken, Germany.
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Choi HS, Jang HJ, Kristensen MK, Kwon TH. TAZ is involved in breast cancer cell migration via regulating actin dynamics. Front Oncol 2024; 14:1376831. [PMID: 38774409 PMCID: PMC11106448 DOI: 10.3389/fonc.2024.1376831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/11/2024] [Indexed: 05/24/2024] Open
Abstract
Background Cancer metastasis is dependent on cell migration. Several mechanisms, including epithelial-to-mesenchymal transition (EMT) and actin fiber formation, could be involved in cancer cell migration. As a downstream effector of the Hippo signaling pathway, transcriptional coactivator with PDZ-binding motif (TAZ) is recognized as a key mediator of the metastatic ability of breast cancer cells. We aimed to examine whether TAZ affects the migration of breast cancer cells through the regulation of EMT or actin cytoskeleton. Methods MCF-7 and MDA-MB-231 cells were treated with siRNA to attenuate TAZ abundance. Transwell migration assay and scratch wound healing assay were performed to study the effects of TAZ knockdown on cancer cell migration. Fluorescence microscopy was conducted to examine the vinculin and phalloidin. Semiquantitative immunoblotting and quantitative real-time PCR were performed to study the expression of small GTPases and kinases. Changes in the expression of genes associated with cell migration were examined through next-generation sequencing. Results TAZ-siRNA treatment reduced TAZ abundance in MCF-7 and MDA-MB-231 breast cancer cells, which was associated with a significant decrease in cell migration. TAZ knockdown increased the expression of fibronectin, but it did not exhibit the typical pattern of EMT progression. TGF-β treatment in MDA-MB-231 cells resulted in a reduction in TAZ and an increase in fibronectin levels. However, it paradoxically promoted cell migration, suggesting that EMT is unlikely to be involved in the decreased migration of breast cancer cells in response to TAZ suppression. RhoA, a small Rho GTPase protein, was significantly reduced in response to TAZ knockdown. This caused a decrease in the expression of the Rho-dependent downstream pathway, i.e., LIM kinase 1 (LIMK1), phosphorylated LIMK1/2, and phosphorylated cofilin, leading to actin depolymerization. Furthermore, myosin light chain kinase (MLCK) and phosphorylated MLC2 were significantly decreased in MDA-MB-231 cells with TAZ knockdown, inhibiting the assembly of stress fibers and focal adhesions. Conclusion TAZ knockdown inhibits the migration of breast cancer cells by regulating the intracellular actin cytoskeletal organization. This is achieved, in part, by reducing the abundance of RhoA and Rho-dependent downstream kinase proteins, which results in actin depolymerization and the disassembly of stress fibers and focal adhesions.
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Affiliation(s)
- Hong Seok Choi
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
| | - Hyo-Ju Jang
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
| | - Mathilde K. Kristensen
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
- Faculty of Health, Medicine, Aarhus University, Aarhus, Denmark
| | - Tae-Hwan Kwon
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Taegu, Republic of Korea
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Raja Xavier JP, Rianna C, Hellwich E, Nikolou I, Lankapalli AK, Brucker SY, Singh Y, Lang F, Schäffer TE, Salker MS. Excessive endometrial PlGF- Rac1 signalling underlies endometrial cell stiffness linked to pre-eclampsia. Commun Biol 2024; 7:530. [PMID: 38704457 PMCID: PMC11069541 DOI: 10.1038/s42003-024-06220-7] [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: 04/26/2023] [Accepted: 04/19/2024] [Indexed: 05/06/2024] Open
Abstract
Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides other biochemical and molecular regulators. In this study, we investigated how the Placental Growth Factor (PlGF) changes endometrial mechanics by modifying the actin cytoskeleton at the maternal interface. We explored the global effects of PlGF in endometrial stromal cells (EnSCs) using the concerted approach of proteomics, atomic force microscopy (AFM), and electrical impedance spectroscopy (EIS). Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization-associated proteins in EnSCs. Rac1 and PAK1 transcript levels, activity, and actin polymerization were significantly increased with PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF treatment. The additive effect of PlGF on actin polymerization was suppressed with siRNA-mediated inhibition of Rac1, PAK1, and WAVE2. Interestingly, the increase in cell stiffness by PlGF treatment was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion. Taken together, aberrant PlGF levels in the endometrium can contribute to an altered pre-pregnancy maternal microenvironment and offer a unifying explanation for the pathological changes observed in conditions such as pre-eclampsia (PE).
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Affiliation(s)
| | - Carmela Rianna
- Institute of Applied Physics, University of Tübingen, Tübingen, Germany
| | - Emily Hellwich
- Institute of Applied Physics, University of Tübingen, Tübingen, Germany
| | - Iliana Nikolou
- Department of Women's Health, University of Tübingen, Tübingen, Germany
| | | | - Sara Y Brucker
- Department of Women's Health, University of Tübingen, Tübingen, Germany
| | - Yogesh Singh
- Department of Women's Health, University of Tübingen, Tübingen, Germany
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Tilman E Schäffer
- Institute of Applied Physics, University of Tübingen, Tübingen, Germany
| | - Madhuri S Salker
- Department of Women's Health, University of Tübingen, Tübingen, Germany.
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Gu Q, An Y, Xu M, Huang X, Chen X, Li X, Shan H, Zhang M. Disulfidptosis, A Novel Cell Death Pathway: Molecular Landscape and Therapeutic Implications. Aging Dis 2024; 16:917-945. [PMID: 38739940 PMCID: PMC11964418 DOI: 10.14336/ad.2024.0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024] Open
Abstract
Programmed cell death is pivotal for several physiological processes, including immune defense. Further, it has been implicated in the pathogenesis of developmental disorders and the onset of numerous diseases. Multiple modes of programmed cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis, have been identified, each with their own unique characteristics and biological implications. In February 2023, Liu Xiaoguang and his team discovered "disulfidptosis," a novel pathway of programmed cell death. Their findings demonstrated that disulfidptosis is triggered in glucose-starved cells exhibiting high expression of a protein called SLC7A11. Furthermore, disulfidptosis is marked by a drastic imbalance in the NADPH/NADP+ ratio and the abnormal accumulation of disulfides like cystine. These changes ultimately lead to the destabilization of the F-actin network, causing cell death. Given that high SLC7A11 expression is a key feature of certain cancers, these findings indicate that disulfidptosis could serve as the basis of innovative anti-cancer therapies. Hence, this review delves into the discovery of disulfidptosis, its underlying molecular mechanisms and metabolic regulation, and its prospective applications in disease treatment.
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Affiliation(s)
- Qiuyang Gu
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Yumei An
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Mingyuan Xu
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Xinqi Huang
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Xueshi Chen
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Xianzhe Li
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Haiyan Shan
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Mingyang Zhang
- Institute of Forensic Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
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Yu P, Han Y, Meng L, Tian Y, Jin Z, Luo J, Han C, Xu W, Kong L, Zhang C. Exosomes derived from pulmonary metastatic sites enhance osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS. Acta Pharm Sin B 2024; 14:2039-2056. [PMID: 38799644 PMCID: PMC11119511 DOI: 10.1016/j.apsb.2024.01.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/22/2023] [Accepted: 01/05/2024] [Indexed: 05/29/2024] Open
Abstract
Osteosarcoma, a prevalent primary malignant bone tumor, often presents with lung metastases, severely impacting patient survival rates. Extracellular vesicles, particularly exosomes, play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions. However, the communication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure, with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown. This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site. This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate (MARCKS) expression. Addressing this phenomenon, in this study we employ cationic bovine serum albumin (CBSA) to form nanoparticles (CBSA-anta-194/215) via electrostatic interaction with antagomir-miR-194/215. These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles (anta-194/215@Exo) targeting osteosarcoma lung metastatic sites. Intervention with bioengineered exosome mimetics (anta-194/215@Exo) not only impedes osteosarcoma progression but also significantly prolongs the lifespan of tumor-bearing mice. These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS, making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.
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Affiliation(s)
- Pei Yu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yubao Han
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Lulu Meng
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yanyuan Tian
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Zhiwei Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Jun Luo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Chao Han
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Wenjun Xu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Lingyi Kong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Chao Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
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Cheng Y, Li Q, Sun G, Li T, Zou Y, Ye H, Wang K, Shi J, Wang P. Serum anti-CFL1, anti-EZR, and anti-CYPA autoantibody as diagnostic markers in ovarian cancer. Sci Rep 2024; 14:9757. [PMID: 38684875 PMCID: PMC11058243 DOI: 10.1038/s41598-024-60544-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/24/2024] [Indexed: 05/02/2024] Open
Abstract
The purpose of this study was to identify novel autoantibodies against tumor-associated antigens (TAAs) and explore a diagnostic panel for Ovarian cancer (OC). Enzyme-linked immunosorbent assay was used to detect the expression of five anti-TAA autoantibodies in the discovery (70 OC and 70 normal controls) and validation cohorts (128 OC and 128 normal controls). Machine learning methods were used to construct a diagnostic panel. Serum samples from 81 patients with benign ovarian disease were used to identify the specificity of anti-TAA autoantibodies for OC. In both the discovery and validation cohorts, the expression of anti-CFL1, anti-EZR, anti-CYPA, and anti-PFN1 was higher in patients with OC than that in normal controls. The area under the receiver operating characteristic curve, sensitivity, and specificity of the panel containing anti-CFL1, anti-EZR, and anti-CYPA were 0.762, 55.56%, and 81.31%. The panel identified 53.06%, 53.33%, and 51.11% of CA125 negative, HE4 negative and the Risk of Ovarian Malignancy Algorithm negative OC patients, respectively. The combination of the three anti-TAA autoantibodies can serve as a favorable diagnostic tool for OC and has the potential to be a complementary biomarker for CA125 and HE4 in the diagnosis of ovarian cancer.
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Affiliation(s)
- Yifan Cheng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Qing Li
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Guiying Sun
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Yuanlin Zou
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan Province, China.
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, China.
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Wang L, Liu Y, Tai J, Dou X, Yang H, Li Q, Liu J, Yan Z, Liu X. Transcriptome and single-cell analysis reveal disulfidptosis-related modification patterns of tumor microenvironment and prognosis in osteosarcoma. Sci Rep 2024; 14:9186. [PMID: 38649690 PMCID: PMC11035678 DOI: 10.1038/s41598-024-59243-9] [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: 04/03/2023] [Accepted: 04/08/2024] [Indexed: 04/25/2024] Open
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor with high pathological heterogeneity. Our study aimed to investigate disulfidptosis-related modification patterns in OS and their relationship with survival outcomes in patients with OS. We analyzed the single-cell-level expression profiles of disulfidptosis-related genes (DSRGs) in both OS microenvironment and OS subclusters, and HMGB1 was found to be crucial for intercellular regulation of OS disulfidptosis. Next, we explored the molecular clusters of OS based on DSRGs and related immune cell infiltration using transcriptome data. Subsequently, the hub genes of disulfidptosis in OS were screened by applying multiple machine models. In vitro and patient experiments validated our results. Three main disulfidptosis-related molecular clusters were defined in OS, and immune infiltration analysis suggested high immune heterogeneity between distinct clusters. The in vitro experiment confirmed decreased cell viability of OS after ACTB silencing and higher expression of ACTB in patients with lower immune scores. Our study systematically revealed the underlying relationship between disulfidptosis and OS at the single-cell level, identified disulfidptosis-related subtypes, and revealed the potential role of ACTB expression in OS disulfidptosis.
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Affiliation(s)
- Linbang Wang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, People's Republic of China
| | - Yu Liu
- Department of Orthopaedics, Peking University Third Hospital, Beijing, People's Republic of China
| | - Jiaojiao Tai
- Department of Orthopedics, Honghui Hospital, Xi'an Jiaotong University, No. 555, Youyi Road, Beilin District, Xi'an, 710054, Shaanxi, People's Republic of China
| | - Xinyu Dou
- Department of Orthopaedics, Peking University Third Hospital, Beijing, People's Republic of China
| | - Hongjuan Yang
- School of Foreign Studies, Xi'an Medical University, Xi'an, 710054, Shaanxi, People's Republic of China
| | - Qiaochu Li
- Department of Orthopedic Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Jingkun Liu
- Department of Orthopedics, Honghui Hospital, Xi'an Jiaotong University, No. 555, Youyi Road, Beilin District, Xi'an, 710054, Shaanxi, People's Republic of China.
| | - Ziqiang Yan
- Department of Orthopedics, Honghui Hospital, Xi'an Jiaotong University, No. 555, Youyi Road, Beilin District, Xi'an, 710054, Shaanxi, People's Republic of China.
| | - Xiaoguang Liu
- Department of Orthopaedics, Peking University Third Hospital, Beijing, People's Republic of China.
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45
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Sun J, Jiao Y, Pan F, Cheng SH, Sun D. A High-Throughput Microdroplet-Based Single Cell Transfection Method for Gene Knockout Based on the CRISPR/Cas9 System. IEEE Trans Nanobioscience 2024; 23:378-388. [PMID: 38442045 DOI: 10.1109/tnb.2024.3373597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
The efficient application of the newly developed gene-editing method CRISPR/Cas9 requires more accurate intracellular gene delivery. Traditional delivery approaches, such as lipotransfection and non-viral delivery methods, must contend with major problems to overcome the drawbacks of low efficiency, high toxicity, and cell-type dependency. The high-throughput microdroplet-based single-cell transfection method presented herein provides an alternative method for delivering genome-editing reagents into single living cells. By accurately controlling the number of exogenous plasmids in microdroplets, this method can achieve high-efficiency delivery of nucleic acids to different types of single cells. This paper presents a high-throughput quantitative DNA transfection method for single cells and explores the optimal DNA transfection conditions for specific cell lines. The transfection efficiency of cells at different concentrations of DNA in microdroplets is measured. Under the optimized transfection conditions, the method is used to construct gene-knockout cancer cell lines to determine specific gene functions through the CRISPR/Cas9 knockout system. In a case study, the migration ability of TRIM72 knockout cancer cells is inhibited, and the tumorigenicity of cells in a zebrafish tumor model is reduced. A single-cell microfluidic chip is designed to achieve CRISPR/Cas9 DNA transfection, dramatically improving the transfection efficiency of difficult-to-transfect cells. This research demonstrates that the microdroplet method developed herein has a unique advantage in CRISPR/Cas9 gene-editing applications.
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46
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Khathayer F, Mikael M. Mocetinostat as a novel selective histone deacetylase (HDAC) inhibitor in the promotion of apoptosis in glioblastoma cell line C6 and T98G. RESEARCH SQUARE 2024:rs.3.rs-4170668. [PMID: 38645087 PMCID: PMC11030514 DOI: 10.21203/rs.3.rs-4170668/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Histon deacetylase (HDAC) enzyme is one of the enzymes involved in regulating gene expression and epigenetic alternation of cells by removing acetyl groups from lysine residue on a histone, allowing the histones to wrap the DNA more tightly and suppressing a tumor-suppressing gene. HDAC inhibitors play an important role in inhibiting the proliferation of tumor cells by restricting the mechanism of action of HDAC enzyme, leading to the addition of acetyl groups to lysine. Mocetinostat, also known by its chemical name (MGCD0103), is a novel isotype selective HDAC enzyme that explicitly targets HDAC isoforms inhibiting Class1(HDAC 1,2,3,8) and Class IV (HDAC11) enzymes. It was approved for treating the phase II trial of Hodgkin's lymphoma in 2010. Our study revealed that different doses of Mocetinostat inhibit the growth of glioblastoma cells, metastasis, and angiogenesis and induce the apoptosis and differentiation of glioblastoma cells C6 and T98G. Western blot has shown that MGCD0103 has many biological activities to control glioblastoma cancer cells. MGCD0103 can modulate the molecular mechanism for several pathways in cells, such as inhibition of the PI3K/AKT pathway and suppression of HDAC1 enzyme activity in charge of many biological processes in the initiation and progression of cancer. The high doses of Mocetinostat drug significantly induce apoptosis and suppress cancer cell proliferation through increased pro-apoptotic proteins (BAX) and a down level of anti-apoptotic proteins(Bid, Bcl2). Also, the mocetinostat upregulated the expression of the tumor suppressor gene and downregulated the gene expression of the E2f1 transcription factor. Additionally, MGCDO103-induced differentiation was facilitated by activating the differentiation marker GFAP and preventing the undifferentiation marker from expression (Id2, N-Myc). The MGCD0103 is a potent anticancer drug crucial in treating glioblastoma cells.
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Yapp C, Nirmal AJ, Zhou F, Maliga Z, Tefft JB, Llopis PM, Murphy GF, Lian CG, Danuser G, Santagata S, Sorger PK, Human Tumour Atlas Network. Multiplexed 3D Analysis of Immune States and Niches in Human Tissue. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.11.10.566670. [PMID: 38014052 PMCID: PMC10680601 DOI: 10.1101/2023.11.10.566670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Tissue homeostasis and the emergence of disease are controlled by changes in the proportions of resident and recruited cells, their organization into cellular neighbourhoods, and their interactions with acellular tissue components. Highly multiplexed tissue profiling (spatial omics)1 makes it possible to study this microenvironment in situ, usually in 4-5 micron thick sections (the standard histopathology format)2. Microscopy-based tissue profiling is commonly performed at a resolution sufficient to determine cell types but not to detect subtle morphological features associated with cytoskeletal reorganisation, juxtracrine signalling, or membrane trafficking3. Here we describe a high-resolution 3D imaging approach able to characterize a wide variety of organelles and structures at sub-micron scale while simultaneously quantifying millimetre-scale spatial features. This approach combines cyclic immunofluorescence (CyCIF) imaging4 of over 50 markers with confocal microscopy of archival human tissue thick enough (30-40 microns) to fully encompass two or more layers of intact cells. 3D imaging of entire cell volumes substantially improves the accuracy of cell phenotyping and allows cell proximity to be scored using plasma membrane apposition, not just nuclear position. In pre-invasive melanoma in situ5, precise phenotyping shows that adjacent melanocytic cells are plastic in state and participate in tightly localised niches of interferon signalling near sites of initial invasion into the underlying dermis. In this and metastatic melanoma, mature and precursor T cells engage in an unexpectedly diverse array of juxtracrine and membrane-membrane interactions as well as looser "neighbourhood" associations6 whose morphologies reveal functional states. These data provide new insight into the transitions occurring during early tumour formation and immunoediting and demonstrate the potential for phenotyping of tissues at a level of detail previously restricted to cultured cells and organoids.
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Affiliation(s)
- Clarence Yapp
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA
| | - Ajit J. Nirmal
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Felix Zhou
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Zoltan Maliga
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
| | - Juliann B. Tefft
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA
| | - Paula Montero Llopis
- Microscopy Resources on the North Quad (MicRoN), Harvard Medical School, Boston, MA 02115, USA
| | - George F. Murphy
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Christine G. Lian
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Gaudenz Danuser
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Sandro Santagata
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
| | - Peter K. Sorger
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- Ludwig Centre at Harvard, Harvard Medical School, Boston, MA, 02115, USA
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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Wang Y, Guan ZY, Shi SW, Jiang YR, Zhang J, Yang Y, Wu Q, Wu J, Chen JB, Ying WX, Xu QQ, Fan QX, Wang HF, Zhou L, Wang L, Fang J, Pan JZ, Fang Q. Pick-up single-cell proteomic analysis for quantifying up to 3000 proteins in a Mammalian cell. Nat Commun 2024; 15:1279. [PMID: 38341466 PMCID: PMC10858870 DOI: 10.1038/s41467-024-45659-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ~1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a mammalian cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 2449-3500, 2278-3257 and 1621-2904 protein groups are quantified in single A549 cells (n = 37), HeLa cells (n = 44) and U2OS cells (n = 27) under the DIA (MBR) mode, respectively. Benefiting from the flexible cell picking-up ability, we study HeLa cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.
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Affiliation(s)
- Yu Wang
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
- Single-cell Proteomics Research Center, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 311200, China
- College of Computer Science and Technology, Zhejiang University, Hangzhou, 310027, China
| | - Zhi-Ying Guan
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Shao-Wen Shi
- Single-cell Proteomics Research Center, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 311200, China
| | - Yi-Rong Jiang
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Jie Zhang
- Department of Cell Biology, China Medical University, Shenyang, 110122, China
| | - Yi Yang
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
- Single-cell Proteomics Research Center, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 311200, China
| | - Qiong Wu
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Jie Wu
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Jian-Bo Chen
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Wei-Xin Ying
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Qin-Qin Xu
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Qian-Xi Fan
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
| | - Hui-Feng Wang
- Single-cell Proteomics Research Center, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 311200, China
| | - Li Zhou
- Shanghai Omicsolution Co., Shanghai, 201100, China
| | - Ling Wang
- Shanghai Omicsolution Co., Shanghai, 201100, China
| | - Jin Fang
- Department of Cell Biology, China Medical University, Shenyang, 110122, China
| | - Jian-Zhang Pan
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China
- Single-cell Proteomics Research Center, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 311200, China
| | - Qun Fang
- Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China.
- Single-cell Proteomics Research Center, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 311200, China.
- Key Laboratory of Excited-State Materials of Zhejiang Province, Zhejiang University, Hangzhou, 310007, China.
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Choi YJ, Choi M, Park J, Park M, Kim MJ, Lee JS, Oh SJ, Lee YJ, Shim WS, Kim JW, Kim MJ, Kim YC, Kang KW. Therapeutic strategy using novel RET/YES1 dual-target inhibitor in lung cancer. Biomed Pharmacother 2024; 171:116124. [PMID: 38198957 DOI: 10.1016/j.biopha.2024.116124] [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: 08/04/2023] [Revised: 12/20/2023] [Accepted: 01/02/2024] [Indexed: 01/12/2024] Open
Abstract
Lung cancer represents a significant global health concern and stands as the leading cause of cancer-related mortality worldwide. The identification of specific genomic alterations such as EGFR and KRAS in lung cancer has paved the way for the development of targeted therapies. While targeted therapies for lung cancer exhibiting EGFR, MET and ALK mutations have been well-established, the options for RET mutations remain limited. Importantly, RET mutations have been found to be mutually exclusive from other genomic mutations and to be related with high incidences of brain metastasis. Given these facts, it is imperative to explore the development of RET-targeting therapies and to elucidate the mechanisms underlying metastasis in RET-expressing lung cancer cells. In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer.
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Affiliation(s)
- Yong June Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Munkyung Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Jaewoo Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Miso Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Department of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Myung Jun Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Jae-Sun Lee
- R&D Center, PeLeMed, Co. Ltd., Seoul 06100, Republic of Korea
| | - Su-Jin Oh
- R&D Center, PeLeMed, Co. Ltd., Seoul 06100, Republic of Korea
| | - Young Joo Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Wan Seob Shim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Ji Won Kim
- Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea
| | - Myung Jin Kim
- R&D Center, PeLeMed, Co. Ltd., Seoul 06100, Republic of Korea
| | - Yong-Chul Kim
- R&D Center, PeLeMed, Co. Ltd., Seoul 06100, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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50
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Frascogna C, Mottareale R, La Verde G, Arrichiello C, Muto P, Netti PA, Pugliese M, Panzetta V. Role of the mechanical microenvironment on CD-44 expression of breast adenocarcinoma in response to radiotherapy. Sci Rep 2024; 14:391. [PMID: 38172135 PMCID: PMC10764959 DOI: 10.1038/s41598-023-50473-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
The biological effects of ionizing radiation are exploited in the clinical practice of radiotherapy to destroy tumour cells while sparing the surrounding normal tissue. While most of the radiotherapy research focused on DNA damage and repair, recently a great attention is going to cells' interactions with the mechanical microenvironment of both malignant and healthy tissues after exposure. In fact, the stiffness of the extracellular matrix can modify cells' motility and spreading through the modulation of transmembrane proteins and surface receptors' expression, such as CD-44. CD-44 receptor has held much interest also in targeted-therapy due to its affinity with hyaluronic acid, which can be used to functionalize biodegradable nanoparticles loaded with chemotherapy drugs for targeted therapy. We evaluated changes in CD-44 expression in two mammary carcinoma cell lines (MCF10A and MDA-MB-231) after exposure to X-ray (2 or 10 Gy). To explore the role of the mechanical microenvironment, we mimicked tissues' stiffness with polyacrylamide's substrates producing two different elastic modulus values (0.5 and 15 kPa). We measured a dose dependent increase in CD-44 relative expression in tumour cells cultured in a stiffer microenvironment. These findings highlight a crucial connection between the mechanical properties of the cell's surroundings and the post-radiotherapy expression of surface receptors.
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Affiliation(s)
- Crescenzo Frascogna
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Largo Barsanti e Matteucci 53, 80125, Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Piazzale Vincenzo Tecchio, 80125, Naples, Italy
| | - Rocco Mottareale
- Department of Physics "E. Pancini", University of Naples Federico II, Via Cinthia, 80126, Naples, Italy
| | - Giuseppe La Verde
- Department of Physics "E. Pancini", University of Naples Federico II, Via Cinthia, 80126, Naples, Italy
- Istituto Nazionale di Fisica Nucleare, INFN Sezione di Napoli, Via Cinthia Ed. 6, 80126, Naples, Italy
| | - Cecilia Arrichiello
- Radiotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Via Semmola, 53, 80131, Naples, Italy
| | - Paolo Muto
- Radiotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Via Semmola, 53, 80131, Naples, Italy
| | - Paolo A Netti
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Largo Barsanti e Matteucci 53, 80125, Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Piazzale Vincenzo Tecchio, 80125, Naples, Italy
- Interdisciplinary Research Centre On Biomaterials CRIB, University of Naples Federico II, Piazzale Vincenzo Tecchio, 80125, Naples, Italy
| | - Mariagabriella Pugliese
- Department of Physics "E. Pancini", University of Naples Federico II, Via Cinthia, 80126, Naples, Italy.
- Istituto Nazionale di Fisica Nucleare, INFN Sezione di Napoli, Via Cinthia Ed. 6, 80126, Naples, Italy.
| | - Valeria Panzetta
- Center for Advanced Biomaterials for Healthcare @CRIB, Italian Institute of Technology, Largo Barsanti e Matteucci 53, 80125, Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Piazzale Vincenzo Tecchio, 80125, Naples, Italy
- Interdisciplinary Research Centre On Biomaterials CRIB, University of Naples Federico II, Piazzale Vincenzo Tecchio, 80125, Naples, Italy
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