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.

New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

“…Moreover phosphorylation primes FOXOs polyubiquitination and subsequent proteasomal degradation [ 25 , 151 , 186 ]. Consequently, inhibition of Akt, for example by treatment with S-equol, a secondary metabolite of the natural anticancer isoflavone daidzein, prevents the degradation of FOXO3a and decreased prostate tumor growth [ 189 ]. However, controversial data has been obtained with the less specific inhibitor of the upstream kinase PI3K, LY294002 in other cell types suggesting cell type-dependent or Akt-independent mechanisms [ 151 , 190 ].…”

Daidzein inhibits choriocarcinoma proliferation by arresting cell cycle at G1 phase through suppressing ERK pathway in vitro and in vivo

“…Previously, daidzein garnered interest in its antitumor activity especially in proliferation inhibition and apoptosis induction. Daidzein induces apoptosis in prostate cancer cells (LnCap and PC3) (16), and its metabolite inhibits prostate cancer growth in vitro and in vivo (17).…”

Ophiopogonin D' induces RIPK1‑dependent necroptosis in androgen‑dependent LNCaP prostate cancer cells

“…Cells were incubated in a stable, humidified environment at 37˚C with 5% CO 2 and were passaged every 2-3 days when they became confluent. The three cell lines were cultured in their own special medium supplemented with 10% FBS as previously described (22). Apoptosis assay.…”