Activation of FOXO1 is critical for the anticancer effect of methylseleninic acid in prostate cancer cells.

BACKGROUND Previous studies have demonstrated that physiological concentrations of methylseleninic acid (MSA) inhibits the growth of prostate cancer cells. The growth inhibitory effect could be attributed to cell cycle block and apoptosis induction. The current study was designed to investigate the involvement of forkhead box O1 (FOXO1) in the anticancer effect of MSA. METHODS LNCaP and LAPC-4 cells were treated with 10 µM MSA for various time points, and the expression of FOXO1 was analyzed by qRT-PCR and Western blotting. FOXO1 activity was determined by a luciferase construct containing FOXO binding sites. The trans-activation activity of the androgen receptor (AR) was determined by the ARE-luciferase assay. FOXO1 gene silencing was achieved by using a small interfering RNA (siRNA). RESULTS MSA treatment led to a rapid and robust increase of FOXO1 expression, as well as an increase of the FOXO1 transcriptional activity. Blocking FOXO1 activation by gene silencing abolished apoptosis induction by MSA, suggesting FOXO1 plays a critical role in mediating the apoptotic effect of MSA. Recent studies have shown that FOXO1 and AR antagonize the actions of each other. We examined the consequence of FOXO1 induction on AR activity. Consistent with previous reports, we found that ectopic expression of FOXO1 suppressed the transcriptional activity of AR. Furthermore, FOXO1 silencing attenuated MSA suppression of AR activity, suggesting that FOXO1 induction contributes to suppression of AR signaling by MSA. CONCLUSIONS In prostate cancer cells, MSA activates the FOXO1 signaling pathway. FOXO1 activation is critical for the anticancer effects of MSA. Prostate 70:1265–1273, 2010. © 2010 Wiley-Liss, Inc.