Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT.
Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT.
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二甲双胍通过靶向 TGF-β 1/STAT3 轴调节的 EMT 逆转前列腺癌对恩杂鲁胺的耐药性
DOI：
10.1038/cddis.2017.417
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发表时间：
2017-08-24
影响因子：
9
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Liu Q;Tong D;Liu G;Xu J;Do K;Geary K;Zhang D;Zhang J;Zhang Y;Li Y;Bi G;Lan W;Jiang J
新开发的第二代抗雄激素药物Enzalutamide虽然可以显著抑制前列腺癌进展，但主要由于Enzalutamide耐药的发生，仅延长了前列腺癌患者的生存期4-6个月。以往关于AR拮抗剂抗性的研究大多集中在AR信号传导上。因此，Enzalutamide耐药的非AR途径在很大程度上仍然未知。通过使用C4-2、CWR 22 Rv 1和LNCaP细胞系，以及Enzalutamide或二甲双胍单独或联合治疗的CWR 22 Rv 1异种移植小鼠，我们证明了二甲双胍能够逆转Enzalutamide耐药性并恢复CWR 22 Rv 1异种移植物对Enzalutamide的敏感性。我们发现二甲双胍通过抑制EMT减轻了对Enzalutamide的耐药性。此外，基于二甲双胍对STAT 3激活和TGF-β1表达的影响，我们提出二甲双胍通过靶向TGF-β1/STAT 3轴发挥其作用。这些结果表明，二甲双胍与Enzalutamide联合治疗可能是治疗去势抵抗性前列腺癌的更有效的治疗策略。
Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4–6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-β1, we propose that metformin exerts its effects by targeting the TGF-β1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer.
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影响因子：
9
作者：
通讯作者：
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影响因子：
9.2
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