摘要
FOXO3a是肿瘤抑制功能的转录因子,在前列腺癌中起重要作用。大豆苷元,是目前以大豆为基础的食品里的的大豆异黄酮之一,已被证明在体内外具有抗肿瘤作用。本文研究了大豆苷元经肠道菌群的代谢产物-S型雌马酚对人类前列腺癌细胞系LNCaP,DU145和PC3的抑制作用。我们的研究结果表明,S型雌马酚和R型雌马酚抑制了这三类细胞株的生长。更多的研究表明,S型雌马酚通过下调细胞周期蛋白B1和CDK1和上调CDK抑制剂(p21和p27),在PC3细胞引起细胞周期阻滞在G2/M期,以及通过上调Fas配体(FasL)和促凋亡因子Bim的表达诱导了细胞凋亡。此外, S型雌马酚提高了FOXO3a的表达,降低了p-FOXO3a的表达和增强了FoxO3a的核稳定性。S型雌马酚还减少了作为FOXO3a的E3泛素连接酶的MDM2的表达,从而防止p-FOXO3a被蛋白酶体降解。机理研究表明,S型雌马酚以Akt / FoxO3a通路为靶点,这对前列腺癌细胞的生存、细胞周期的进程和细胞凋亡是很重要的。此外,S型雌马酚治疗抑制了BALB/c裸鼠前列腺癌PC3移植瘤的生长。总体而言,从目前的研究数据表明,S型雌马酚在体内外具有显著的抗前列腺癌的活性,表明其抗癌作用可能与通过Akt的特异途径和抑制MDM2蛋白表达的FOXO3a活性有关。研究结果不仅让人们更好地了解这种天然抗癌化合物独特的次生代谢产物的的分子机制,而且也为大豆苷元及其类似物作为一种新型的抗癌药物的开发奠定了基础。
关键词: S 型雌马酚,前列腺癌,FoxO3a, Akt,磷酸化
图形摘要
Current Cancer Drug Targets
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.
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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
DOI https://dx.doi.org/10.2174/1568009616666151207105720 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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