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AMC Cancer Research Center, Denver, Colorado 80214 [A. V. G., Y. J. Y., J. L., A. Y. Y., T. J. S., I. V. B.], and Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892 [L. A. L.]

Selenium compounds are potential chemopreventive agents for prostate cancer. There are several proposed mechanisms for their anticancer effect, including enhanced apoptosis of transformed cells. Because the transcription factor nuclear factor-B (NF-B) is often constitutively activated in tumors and is a key antiapoptotic factor in mammalian cells, we tested whether selenium inhibited NF-B activity in prostate cancer cells. In our work, we used sodium selenite and a novel synthetic compound, methylseleninic acid (MSeA), that served as a precursor of the putative active monomethyl metabolite methylselenol. We found that both selenium forms inhibited cell growth and induced apoptosis in DU145 and JCA1 prostate carcinoma cells. Sodium selenite and MeSeA, at the concentrations that induced apoptosis, inhibited NF-B DNA binding induced by tumor necrosis factor- and lipopolysaccharide in DU145 and JCA1 prostate cells. Both compounds also inhibited B.Luciferase reporter activity in prostate cells. A key to NF-B regulation is the inhibitory B (IB) proteins that in response to diverse stimuli are rapidly phosphorylated by IB kinase complex, ubiquitinated, and undergo degradation, releasing NF-B factor. We showed that sodium selenite and MSeA inhibited IB kinase activation and IB- phosphorylation and degradation induced by TNF- and lipopolysaccharide in prostate cells. NF-B blockage by IB- d.n. mutant resulted in the sensitization of prostate carcinoma cells to apoptosis induced by selenium compounds. These results suggest that selenium may target the NF-B activation pathway to exert, at least in part, its cancer chemopreventive effect in prostate.

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