Selenoproteins and Prostate Cancer

摘要

For this postdoctoral fellowship the specific role of selenoproteins (SP) in prostate cancer (PCa) was investigated. First the response of varying allelic identitiesin the SP glutathione peroxidase (GPx-1) to selenium (Se) supplementation was determined. GPx-1 has either a leucine (leu) or proline (pro) amino acid at thei9S codon and cancer risk has been shown to vary depending on the allelic identity. Our investigation showed that the prostate cell line LNCaP containing leuat the 198 codon was more responsive to Se supplementation although its baseline GPx activity was lower compared to cells with a pro at the same codon.These studies have increased our understanding of the effect of genetic variations in GPx-1 on the response to dietary Se and are relevant to the observedeffects of Se in the SELECT trial. Second using the siRNA technique levels of GPx-1 were significantly reduced in LNCaP cells and the effect on DNA damageinvestigated. Compared to control transfectants cells with reduced GPx-1 levels were found to be more susceptible to UVC induced DNA damage as assessedby micronuclel formation. Se Supplementation was more effective in attenuating micronuclel formation in the control compared to GPx knock-downtransfectants suggesting that maximum benefits were achieved through its regulation of GPx-1. Studies in transgenic mice that express reduced levels of SPand an increased risk for PCa indicated that Se supplementation attenuated the progression to high-grade prostatic intraepithelial neoplasia (PIN) in the wildtype but not in the SP deficient animals. This benefit however was not observed with histopathological progression to low-grade PIN or microinvasion.Collectively these studies suggest that Se effects in PCa may in part be mediated through SP.