The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic drug metformin has a synergistic effect with ADT in prostate cancer both in vitro and in vivo. Our results show that longer term exposure to ADT induced senescence associated with p16INK4a and/or p27kip2 induction. The activation of PI3K/AKT and inactivation of AMPK in senescent cells resulted in mTORC1 activation. In addition, the antiapoptotic protein XIAP expression was increased in response to ADT. The addition of metformin following ADT induced apoptosis, attenuated mTOR activation, reduced senescent cell number in vitro, and inhibited tumor growth in prostate cancer patient-derived xenograft models. This study suggests that combining ADT and metformin may be a feasible therapeutic approach to remove persistent prostate cancer cells after ADT.

中文翻译：

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用二甲双胍合成致死代谢靶向雄激素剥夺的前列腺癌细胞

雄激素剥夺疗法 (ADT) 的启动会诱导前列腺癌细胞的易感性，使它们容易受到协同治疗的影响并增加细胞死亡。衰老导致细胞周期停滞，但细胞仍然存活。在这项研究中，我们研究了前列腺癌细胞响应 ADT 衰老的机制，并确定了 FDA 批准的抗糖尿病药物二甲双胍在体外和体内是否与 ADT 在前列腺癌中具有协同作用。我们的结果表明，长期暴露于 ADT 诱导的衰老与 p16INK4a 和/或 p27kip2 诱导相关。衰老细胞中 PI3K/AKT 的激活和 AMPK 的失活导致 mTORC1 激活。此外，抗凋亡蛋白XIAP表达响应ADT而增加。在 ADT 后添加二甲双胍可诱导细胞凋亡，减弱 mTOR 活化，减少体外衰老细胞数量，并抑制前列腺癌患者来源的异种移植模型中的肿瘤生长。这项研究表明，结合 ADT 和二甲双胍可能是一种可行的治疗方法，可以在 ADT 后去除持续存在的前列腺癌细胞。