20

The Nutritional Prevention of Cancer Trial showed that selenium supplementation reduced the incidence of prostate cancer by ~50%. Our previous studies demonstrated a novel mechanism of selenium anticancer action. We found that selenium, in the form of methylseleninic acid, markedly inhibited androgen receptor (AR) expression and transactivation in five human prostate cancer cell lines, irrespective of their AR genotype (wild-type vs. mutant) or sensitivity to androgen-stimulated growth. The suppression of AR signaling occurred well before growth inhibition became evident. In addition, transfection of AR significantly weakened the inhibitory effect of selenium on cell growth and proliferation as well as AR-regulated genes implicated in prostate carcinogenesis, including prostate-specific antigen (PSA). The findings therefore indicated a key role of AR-signaling suppression in mediating the anticancer effect of selenium in prostate cancer. The present study adopted a systematic approach to investigate the underlying mechanisms of selenium suppression of AR signaling. We showed that selenium reduced AR availability by blocking AR transcription, rather than by increasing mRNA degradation. The result from the whole-cell radioligand binding assay indicated that selenium did not alter AR ligand-binding activity. On the other hand, selenium greatly inhibited AR N-C dimerization as assessed by using a mammalian two-hybrid system. Furthermore, selenium suppression of ARtranscriptional activity could also be accounted for by the low abundance of an AR-interacting transcription factor, hepatic nuclear factor 3-alpha (HNF3-alpha), as a result of selenium treatment. In summary, our data suggest that selenium depresses AR signaling through multiple mechanisms, e.g., reducing AR transcription, inhibiting AR dimerization, and decreasing the interaction of AR and coregulators.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA