Vitamin E increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) through unknown mechanisms while Selenium showed no efficacy. We determined the effects of the SELECT supplements on benign (primary), premalignant (RWPE-1) and malignant (LNCaP) prostate epithelial organoids. While the supplements decreased proliferation and induced cell death in cancer organoids, they had no effect on the benign organoids. In contrast, Vitamin E enhanced cell proliferation and survival in the premalignant organoids in a manner that recapitulated the SELECT results. Indeed, while Vitamin E induced a pro-proliferative gene expression signature, Selenium alone or combined with Vitamin E produced an anti-proliferative signature. The premalignant organoids also displayed significant downregulation of glucose transporter and glycolytic gene expression pointing to metabolic alterations. Detached RWPE-1 cells had low ATP levels due to diminished glucose uptake and glycolysis which was rescued by Vitamin E through the activation of fatty acid oxidation (FAO). FAO inhibition abrogated the ATP rescue, diminished survival of the inner matrix detached cells, restoring the normal hollow lumen morphology in Vitamin E treated organoids. Organoid models therefore clarify the paradoxical findings from SELECT and demonstrate that Vitamin E promotes tumorigenesis in the early stages of prostate cancer evolution.
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