Pro-oxidant therapy by a vitamin K precursor targets PI 3-Kinase VPS34 function

Men taking anti-oxidant vitamin E supplements have increased prostate cancer (PC) risk. Whether pro- oxidants protect from PC remained unclear. We show that a pro-oxidant vitamin K precursor (MSB) suppresses PC progression in mice killing cells through an oxidative cell death: MSB antagonizes the essential class III 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 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. Overall design: Mouse embryonic fibroblasts (p53 -/- PTEN -/-) were treated with MSB (0, 10, 20 µM) or erastin (0, 0.15, 0.3 µM), in four replicates. RNA was extracted and transcriptome profiles generated.