Homeostatic housecleaning effect of selenium: Evidence that noncytotoxic oxidant‐induced damage sensitizes prostate cancer cells to organic selenium‐triggered apoptosis

Abstract

The anti-cancer activity of organic selenium has been most consistently documented at supra-nutritional levels at which selenium-dependent, antioxidant enzymes are maximized in both expression and activity. Thus, there is a strong imperative to identify mechanisms other than antioxidant protection to account for selenium's anti-cancer activity. In vivo work in dogs showed that dietary selenium supplementation decreased DNA damage but increased apoptosis in the prostate, leading to a new hypothesis: Organic selenium exerts its cancer preventive effect by selectively increasing apoptosis in DNA-damaged cells. Here, we test whether organic selenium (methylseleninic acid; MSA) triggers more apoptosis in human and canine prostate cancer cells that have more DNA damage (strand breaks) created by hydrogen-peroxide (H₂O₂) at noncytotoxic doses prior to MSA exposure. Apoptosis triggered by MSA was significantly higher in H₂O₂-damaged cells. A supra-additive effect was observed--the extent of MSA-triggered apoptosis in H₂O₂-damaged cells exceeded the sum of apoptosis induced by MSA or H₂O₂ alone. However, neither the persistence of H₂O₂-induced DNA damage, nor the activation of mitogen-activated protein kinases was required to sensitize cells to MSA-triggered apoptosis. Our results document that selenium can exert a "homeostatic housecleaning" effect--a preferential elimination of DNA-damaged cells. This work introduces a new and potentially important perspective on the anti-cancer action of selenium in the aging prostate that is independent of its role in antioxidant protection.