Forkhead box O3 (FOXO3a) is a
transcription factor with
tumor suppressor functions that plays an important role in
prostate cancer.
Daidzein, one of the soy
isoflavones present in soy-based foods, has been shown to exert anti-
tumor effects in vitro and in vivo. We herein investigated the inhibitory effects of S-
equol, an isoflavandiol metabolized from
daidzein by bacterial flora in the intestines, on the LnCaP, DU145 and PC3 human
prostate cancer cell lines. Our results showed that S-
equol and R-
equol inhibited the growth of all three cell lines. Additional studies revealed that S-
equol caused cell cycle arrest in the G2/M phase in PC3 cells by downregulating
Cyclin B1 and CDK1 and upregulating CDK inhibitors (p21 and p27), as well as inducing apoptosis by upregulating
Fas ligand (FasL) and the expression of proapoptotic Bim. Additionally, S-
equol increased the expression of FOXO3a, decreased the expression of p-FOXO3a and enhanced the nuclear stability of FOXO3a. S-
equol also decreased the expression of MDM2, which serves as an
E3 ubiquitin ligase for p-FOXO3a, thus preventing p-FOXO3a degradation by the
proteasome. Mechanistic studies showed that S-
equol targeted the Akt/FOXO3a pathway, which is important for
prostate cancer cell survival, cell cycle progression and apoptosis. Moreover, treatment with S-
equol inhibited the growth of PC3 xenograft
tumors in BALB/c nude mice. Overall, the data from the present study demonstrate that S-
equol has significant anti-
prostate cancer activities in vitro and in vivo, and indicate that its anticancer effects were likely associated with the activation of FOXO3a via an Akt-specific pathway and inhibitory effects on MDM2 expression. The results not only provide a better understanding of the molecular mechanisms of this unique secondary metabolite of a natural anti-
cancer compound, but also provide a basis for the development of
daidzein and its analogs as novel
anticancer agents.