S型雌马酚，天然抗癌异黄酮大豆苷元的次级代谢产物，通过激活Akt / FoxO3a通路在体内外抑制前列腺癌的生长

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:

关键词: S 型雌马酚，前列腺癌，FoxO3a， Akt，磷酸化

摘要: 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.

Cite this article as:

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 , 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, Current Cancer Drug Targets 2016; 16 (5) . https://dx.doi.org/10.2174/1568009616666151207105720