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Although immune-checkpoint inhibitors have been approved for selected cases, clinical trials have not met primary endpoints, driving the need for new options. Voltage-dependent anion channel 1 (VDAC1) regulates mitochondrial–cytosolic metabolic coupling and apoptosis and is overexpressed in bladder cancer. Using siRNA that targets human and mouse VDAC1, the study reduces bladder cancer cell viability, mitochondrial potential, and ATP, suppresses tumor growth in two mouse models, and reprograms metabolism and tumor microenvironment through decreased angiogenesis, matrix remodeling, macrophage recruitment, and inhibited epithelial–mesenchymal transition.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/silencing-the-mitochondrial-gatekeeper-vdac1-as-a-potential-treatment-for-bladder-cancer/339249/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/silencing-the-mitochondrial-gatekeeper-vdac1-as-a-potential-treatment-for-bladder-cancer/339249.png","ImageObject",300,407,{"name":92,"@type":93},"Ava Thompson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":56},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is a new treatment needed for bladder cancer?","Question",{"text":112,"@type":113},"BCG fails in a large fraction of patients and immune-checkpoint inhibitors have not achieved primary endpoints in clinical trials. 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Intravesical delivery of siRNA encapsulated in PLGA-PEI nanoparticles reduced tumor area and muscle invasion while preserving bladder morphology better.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},339249,1790102113,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":56,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1649267921044,"https://us-avatar.wpscdn.com/avatar/1800007509477c92dfb?_k=1786009248482753345","cells  \nArticle  \nSilencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer  \nBelal Alhozeel 1, Swaroop Kumar Pandey 1,†, Anna Shteinfer-Kuzmine 2, Manikandan Santhanam 1,2 and Varda Shoshan-Barmatz 1,2, *  \nCitation: Alhozeel, B.; Pandey, S.K.; Shteinfer-Kuzmine, A.; Santhanam, M.; Shoshan-Barmatz, V. Silencing the Mitochondrial Gatekeeper VDAC1 asa Potential Treatment for Bladder Cancer. Cells 2024, 13, 627. [https://](https://)[ ](https://)[doi.org/10.3390/cells13070627](doi.org/10.3390/cells13070627)  \n[Academic Editor: G](Academic Editor: G)érard Lizard  \nReceived: 18 February 2024  \nRevised: 11 March 2024  \nAccepted: 14 March 2024  \nPublished: 4 April 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [belala@post.bgu.ac.il](belala@post.bgu.ac.il) (B.A.); [pandey.swaroop@gmail.com](pandey.swaroop@gmail.com) (S.K.P.); [santhana@post.bgu.ac.il](santhana@post.bgu.ac.il) (M.S.)  \n2 National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [shteinfe@post.bgu.ac.il](shteinfe@post.bgu.ac.il)  \n* [Correspondence: vardasb@bgu.ac.il](Correspondence: vardasb@bgu.ac.il); Tel.: +972-528795939  \n† Current address: Institute of Applied Sciences & Humanities, Department of Biotechnology, GLA University, Mathura 281406, India.  \nAbstract: The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette–Guérin (BCG) . However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy fora subset of BC patients, these have failed to meet primary endpoints in clinical trials. Thus, it is crucial to find a new treatment. The mitochondrial gatekeeper protein, the voltage-dependent anion channel 1 (VDAC1), mediates metabolic crosstalk between the mitochondria and cytosol and is involved in apoptosis. It is overexpressed in many cancer types, as shown here for BC, pointing to its significance in high-energy-demanding cancer cells. The BC cell lines UM-UC3 and HTB-5 express high VDAC1 levels compared to other cancer cell lines. VDAC1 silencing in these cells using siRNA that recognizes both human and mouse VDAC1 (si-m/hVDAC1-B) reduces cell viability, mitochondria membrane potential, and cellular ATP levels. Here, we used two BC mouse models: subcutaneous UM-UC3 cells and chemically induced BC using the carcinogen N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) . Subcutaneous UM-UC3-derived tumors treated with si-m/hVDAC1 showed inhibited tumor growth and reprogrammed metabolism, as reflected in the reduced expression of metabolism-related proteins, including Glut1, hexokinase, citrate synthase, complex-IV, and ATP synthase, suggesting reduced metabolic activity. Furthermore, si-m/hVDAC1-B reduced the expression levels of cancer-stem-cell-related proteins (cytokeratin-14, ALDH1a), modifying the tumor microenvironment, including decreased angiogenesis, extracellular matrix, tumor-associated macrophages, and inhibited epithelial–mesenchymal transition. The BBN-induced BC mouse model showed a clear carcinoma, with damaged bladder morphology and muscle-invasive tumors. Treatment with si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles that were administered intravesically directly to the bladder showed a decreased tumor area and less bladder morphology destruction and muscle invasion. Overall, the obtained results point to the p","cbCaifvE1pykUn7P","https://ap.wps.com/l/cbCaifvE1pykUn7P","pdf",39951569,23,"English","# Introduction\n## VDAC1 and mitochondrial regulation in bladder cancer\n# Materials and Methods\n## siRNA targeting of VDAC1\n## Mouse models and treatments\n# Results\n## Effects on cancer-cell viability and metabolism\n## Tumor growth inhibition and microenvironment modulation\n# Conclusions","[{\"question\":\"Why is a new treatment needed for bladder cancer?\",\"answer\":\"BCG fails in a large fraction of patients and immune-checkpoint inhibitors have not achieved primary endpoints in clinical trials. This motivates searching for alternative therapeutic targets.\"},{\"question\":\"What role does VDAC1 play in the proposed therapy?\",\"answer\":\"VDAC1 is a mitochondrial gatekeeper that supports metabolic crosstalk between mitochondria and the cytosol and is linked to apoptosis. The article reports elevated VDAC1 in bladder cancer cells and uses its silencing to disrupt cancer metabolism.\"},{\"question\":\"How did VDAC1 silencing affect bladder cancer in mouse models?\",\"answer\":\"In both a subcutaneous UM-UC3 model and a chemically induced BBN model, VDAC1-targeting siRNA inhibited tumor growth and altered metabolism-related and cancer-stem-cell-related proteins. Intravesical delivery of siRNA encapsulated in PLGA-PEI nanoparticles reduced tumor area and muscle invasion while preserving bladder morphology better.\"}]","Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer | PDF",1790028954,58]