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, Špokaitė, Saulė, 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 (October 2024) Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function. Science, 386 (6720). eadk9167. ISSN 0036-8075
Abstract
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.
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