Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Mol Cancer Ther. 2020 Nov;19(11):2278-2287. doi: 10.1158/1535-7163.MCT-19-1141. Epub 2020 Sep 17.
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 and Our results show that longer term exposure to ADT induced senescence associated with p16 and/or p27 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 , 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.
雄激素剥夺疗法（ADT）的启动会使前列腺癌细胞产生易感性，使它们容易受到协同治疗和增强的细胞死亡的影响。衰老会导致细胞周期停滞，但细胞仍然存活。在这项研究中，我们研究了前列腺癌细胞对 ADT 反应时发生衰老的机制，并确定了 FDA 批准的抗糖尿病药物二甲双胍是否与 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 会诱导与 p16 和/或 p27 诱导相关的衰老。衰老细胞中 PI3K/AKT 的激活和 AMPK 的失活导致 mTORC1 的激活。此外，抗凋亡蛋白 XIAP 的表达会对 ADT 做出反应而增加。ADT 后添加二甲双胍会诱导细胞凋亡，减弱 mTOR 激活，减少衰老细胞数量，并抑制前列腺癌患者来源异种移植模型中的肿瘤生长。这项研究表明，联合 ADT 和二甲双胍可能是一种可行的治疗方法，用于去除 ADT 后残留的前列腺癌细胞。
