Abstract
B225
Dietary selenium (Se) supplementation has been reported to be associated with a decreased incidence of some human cancers such as prostate cancer. Se has therefore been suggested to be a promising chemopreventive agent for prostate cancer, but the biological effects of Se on normal or malignant prostate cells have not been well established. Thioredoxin reductase (TR) is a seleno-enzyme responsible for maintaining thioredoxin (Trx)in its reduced form. Because Trx is involved in manycellular processes, TR is likely to be an importantregulatory protein for both normal and transformed cells. Trx is overexpressed in a number of human tumors, and experimental studies have shown that Trx contributes to the growth and the transformed phenotype of some human cancer cells. Thus, TR, by reducing Trx, could play a role in regulating the growth of normal and cancer cells. Our objective was to investigate whether Se affects TrxR activity and whether this is associated with alterations in cell proliferation and apoptosis. In this study, we investigated some of the mechanisms by which Se, in the form of sodium selenite, differentially regulates TR activity and affects cell proliferation and apoptosis in LNCaP prostate cancer cells and immortalized benign BPH-1 prostate epithelial cells. The concentrations of Se used in the medium (1-10 µM) spans the range of blood levels normally found in humans (1 to 2.5 µM) and in humans taking Se supplements (up to 10 µM) and is in the order of human prostate tissue Se concentrations. Exposure of malignant LNCaP cells to 5 µM sodium selenite for 72 h led to a profound S phase arrest and exposure to 10 µM led to both G1 arrest and S phase arrest and to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical hallmarks of apoptosis. In contrast, selenite exposure of benign BPH-1 cells to 5 or 10 µM sodium selenite caused only G1 arrest and only caspase-dependent apoptotic DNA fragmentation, but no S phase arrest or caspase-mediated cleavage of PARP. No effects were found on any parameter studied at Se concentrations below 5 µM. These results suggest that LNCaP cells are hypersensitive and BPH-1 cells resistant to the cytostatic and proapoptotic effects of Se. Ten µM sodium selenite, but not 5 µM or less, decreased thioredoxin reductase activity in LNCaP cells, which may be an early toxic effect on these cells. In contrast, in BPH-1 cells Se caused a dose-dependent increase in cellular TR activity over the entire range of concentrations. It is possible that the increased levels of thioredoxin reductase activity found in benign BPH-1 in response to selenium in the high physiological range is associated with the resistance of these cells to the Se effects on cell growth and apoptosis. Our results suggest that Se may exert its effects on human prostate cancer cells through TR which may thus have a role in cancer prevention by Se.
[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]