Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function

• 成果类型: Article
• 署名作者: Swamynathan, Manojit M.; Kuang, Shan; Watrud, Kaitlin E.; Doherty, Mary R.; Gineste, Charlotte; Mathew, Grinu; Gong, Grace Q.; Cox, Hilary; Cheng, Eileen; Reiss, David; Kendall, Jude; Ghosh, Diya; Reczek, Colleen R.; Zhao, Xiang; Herzka, Tali; Spokaite, Saule; Dessus, Antoine N.; Kim, Seung Tea; Klingbeil, Olaf; Liu, Juan; Nowak, Dawid G.; Alsudani, Habeeb; Wee, Tse-Luen; Park, Youngkyu; Minicozzi, Francesca; Rivera, Keith; Almeida, Ana S.; Chang, Kenneth; Chakrabarty, Ram P.; Wilkinson, John E.; Gimotty, Phyllis A.; Diermeier, Sarah D.; Egeblad, Mikala; Vakoc, Christopher R.; Locasale, Jason W.; Chandel, Navdeep S.; Janowitz, Tobias; Hicks, James B.; Wigler, Michael; Pappin, Darryl J.; Williams, Roger L.; Cifani, Paolo; Tuveson, David A.; Laporte, Jocelyn; Trotman, Lloyd C.
• 署名单位: Cold Spring Harbor Laboratory; State University of New York (SUNY) System; Stony Brook University; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); University of Nebraska System; University of Nebraska Medical Center; MRC Laboratory Molecular Biology; Northwestern University; Feinberg School of Medicine; North Carolina State University; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; NewYork-Presbyterian Hospital; University College Cork; University College Cork; University of Michigan System; University of Michigan; University of Pennsylvania; University of Otago; Johns Hopkins University; University of Southern California
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9563
• DOI: 10.1126/science.adk9167
• 发表日期: 2024-10-25
• 关键词: high-resolution metabolomics; human leukemia-cells; prostate-cancer; phosphatidylinositol 3-phosphate; prolongs survival; induced apoptosis; drug targets; reveals; death; myotubularin

摘要

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of MTM1-the phosphatase antagonist of VPS34-we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.