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.
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.
authors.forename: Zongliang
authors.initials: Z
authors.lastname: Lu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Ya
authors.initials: Y
authors.lastname: Kong
authors.forename: Jiajia
authors.initials: J
authors.lastname: Wang
authors.forename: Wanyuan
authors.initials: W
authors.lastname: Xia
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Hailan
authors.initials: H
authors.lastname: Sun
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Mantian
authors.initials: M
authors.lastname: Mi
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China. hongxiaxu@tmmu.edu.cn.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060754:Equol / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D000071316:Forkhead Box Protein O3; D007529:Isoflavones; D060754:Equol; C004742:daidzein; D051057:Proto-Oncogene Proteins c-akt