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首页> 外文期刊>Endocrinology >Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling
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Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling

机译：二甲双胍通过破坏膜启动的雄激素信号传导抑制前列腺癌细胞中雄激素诱导的IGF-IR上调

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We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR+ LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy.
机译：我们先前已经证明，在前列腺癌细胞中，雄激素通过诱导cAMP响应元件结合蛋白（CREB）激活和依赖雄激素受体的CREB依赖性IGF-IR基因转录来上调IGF-I受体（IGF-IR）（ AR）依赖的膜引发效应。 IGF-IR的这种上调不受经典抗雄激素的阻止，并使细胞对IGF-I诱导的生物学效应敏感。二甲双胍在各种模型中均具有复杂的抗肿瘤功能，并可能抑制肝细胞中的CREB活化。因此，我们评估了二甲双胍是否会影响雄激素依赖性IGF-IR的上调。在AR + LNCaP前列腺癌细胞中，我们发现二甲双胍抑制雄激素诱导的CRE活性和IGF-IR基因转录。 CRE活性需要形成一个CREB-CREB结合蛋白-CREB调控的转录共激活因子2（CRTC2）复合物，该复合物随后被Ser133-CREB磷酸化。二甲双胍抑制Ser133-CREB磷酸化并诱导CREB辅助因子CRTC2的核排斥，从而使CREB-CREB结合蛋白-CRTC2复合体解离并阻断其转录活性。与二甲双胍作用相似，CRTC2沉默抑制了IGF-1R启动子活性。此外，二甲双胍通过抑制AR磷酸化及其与c-Src的结合，阻断了AR向雷帕霉素/ p70S6激酶途径的哺乳动物靶标的膜启动信号。 AMPK信号也有一定程度的参与。通过抑制雄激素依赖性IGF-1R的上调，二甲双胍减少了IGF-1介导的LNCaP细胞的增殖。这些结果表明，在前列腺癌细胞中，二甲双胍通过破坏负责IGF-IR上调的膜启动性AR作用来抑制IGF-I介导的生物学作用，并表明二甲双胍可以代表经典抗雄激素疗法的有用辅助剂。

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