Studies on the mechanisms of the prostate cancer protective effect of dietary selenium

There is considerable interest among scientists and the public in determining whether daily supplementation with the essential trace mineral selenium can substantively reduce the incidence of prostate cancer. It is at supra-nutritional levels that the anti-cancer activity of organic selenium has been most consistently documented – levels at which the selenium-dependent, antioxidant enzyme glutathione peroxidase and other selenoproteins are maximized in both expression and activity. This means there is a strong imperative to identify mechanisms other than antioxidant protection to account for selenium’s anti-cancer activity. Previously, our laboratory showed in elderly dogs – the only non-human, animal model of spontaneous prostate cancer – that supplementation with organic selenium could significantly lower DNA damage while increasing apoptosis in the prostate. Moreover, the relationship between selenium status and DNA damage was U-shaped and paralleled the dose-response between selenium status and prostate cancer risk reduction in men. From these findings, we hypothesized that selenium exerts its anticancer effect by preferentially triggering apoptosis in DNA damaged prostate cells. To test this hypothesis in the laboratory, human and canine prostate cancer cells were exposed to hydrogen peroxide (H2O2) at non-cytotoxic doses to create cell populations differing in the extent of DNA damage (measured as DNA strand breaks), then cells were treated with organic selenium in the form of methylseleninic acid (MSA). In both DU-145 human and TR5P canine prostate cancer cells, selenium triggered higher apoptosis in H2O2-damaged cells than the sum of apoptosis induced by selenium or H2O2 alone. We concluded from this supra-additive effect that oxidative damage sensitizes prostatic cells to organic selenium-triggered apoptosis. In contrast, we found apoptosis triggered by inorganic selenium (selenite) was not increased in oxidatively damaged cells. The persistence of H2O2-induced DNA damage was not required to sensitize cells to MSA-triggered apoptosis, suggesting a critical role for signaling pathways downstream from oxidative DNA damage. The influence of H2O2-induced DNA damage on antiapoptotic signaling (mediated by Akt, Erk, and survivin) and pro-apoptotic signaling (mediated by JNK and p38) was studied. However, evaluation of these five pathways – suggested by the work of previous investigators studying selenium and apoptosis – could not provide a simple mechanistic explanation for how oxidative damage sensitizes prostate cells to selenium-triggered apoptosis. Finally, we returned to the in vivo data from the dog study to analyze whether the dose-response relationship between selenium status and apoptosis is U-shaped. We found dogs with moderate selenium status (0.67 – 0.92 ppm in toenails) had the highest apoptosis and lowest DNA damage in the prostate. Taken together, the results from our in vitro and in vivo studies increase confidence that dietary supplementation with organic selenium can exert anti-cancer activity in the prostate by preferentially triggering apoptosis in DNA-damaged cells, a process we refer to as “homeostatic housecleaning”. These results stimulate revisionist thinking about selenium and prostate cancer prevention – moving away from the protection of cells against oxidative damage, moving toward the preferential triggering of apoptosis in damaged cells. These findings have potentially far-reaching implications for guiding future progress on mechanisms, personalized cancer prevention, and cancer prevention trial design