Title:S-equol, a Secondary Metabolite of Natural Anticancer Isoflavone Daidzein, Inhibits Prostate Cancer Growth In Vitro and In Vivo, Though Activating the Akt/FOXO3a Pathway
Volume: 16
Issue: 5
Author(s): Zongliang Lu, Rui Zhou, Ya Kong, Jiajia Wang, Wanyuan Xia, Jing Guo, Jie Liu, Hailan Sun, Kai Liu, Jian Yang, Mantian Mi and Hongxia Xu
Affiliation:
Keywords:
S-equol, prostate cancer, FOXO3a, Akt, phosphorylation.
Abstract: 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.
