Department of Urology, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
Biochem Biophys Res Commun. 2018 Jul 12;502(2):187-193. doi: 10.1016/j.bbrc.2018.05.142. Epub 2018 May 24.
Aspirin is a novel chemopreventive agent against malignancy. However, outcomes of aspirin monotherapy of renal cell carcinoma (RCC) are inconsistent across studies. ABT-737, an BH3 mimetic inhibitor, is also a promising antitumor drug. Cancer cells including those from RCC, that have high levels of Mcl-1, are refractory to ABT-737-induced apoptosis. We here investigated how aspirin treatment modulates the ABT-737-induced apoptosis. Using the in vitro model of human 786-O cells, we showed that aspirin had sensitized cells to ABT-737 induced apoptosis. Such aspirin-induced changes of ABT-737 resistance was accompanied by a host of biochemical events like protein phosphatase 2A (PP2A) activation, AKT dephosphorylation, Mcl-1/FLICE inhibiting protein (FLIP)/XIAP downregulation, and Bax mitochondrial redistribution. The PP2A inhibitor, okadaic acid, was able to reverse the apirin-induced apoptotic changes. Apart from the aspirin treatment, Mcl-1 silencing also rendered cells vulnerable to ABT-737 induced apoptosis. Since PP2A, Akt, and Mcl-1 play critical roles in RCC malignancy and treatment resistance, our present study showed that aspirin, an alternative adjuvant agent, had recalled ABT-737 sensitivity in the RCC cells through processes involving the PP2A/Akt/Mcl-1 axis.
阿司匹林是一种新型的恶性肿瘤化学预防剂。然而，阿司匹林单药治疗肾细胞癌（RCC）的结果在不同的研究中并不一致。ABT-737 是一种 BH3 模拟抑制剂，也是一种很有前途的抗肿瘤药物。包括 RCC 在内的癌细胞，其 Mcl-1 水平较高，对 ABT-737 诱导的细胞凋亡具有抗性。我们在此研究了阿司匹林治疗如何调节 ABT-737 诱导的细胞凋亡。使用人 786-O 细胞的体外模型，我们表明阿司匹林使细胞对 ABT-737 诱导的细胞凋亡敏感。阿司匹林引起的 ABT-737 耐药性改变伴随着一系列生化事件，如蛋白磷酸酶 2A（PP2A）激活、AKT 去磷酸化、Mcl-1/Fas 相关死亡结构域蛋白（FLICE）抑制蛋白（FLIP）/X 连锁凋亡抑制蛋白（XIAP）下调和 Bax 线粒体重分布。PP2A 抑制剂 okadaic 酸能够逆转阿司匹林诱导的凋亡变化。除了阿司匹林治疗外，Mcl-1 沉默也使细胞对 ABT-737 诱导的细胞凋亡敏感。由于 PP2A、Akt 和 Mcl-1 在 RCC 恶性肿瘤和治疗耐药性中发挥着关键作用，我们的研究表明，阿司匹林作为一种替代辅助药物，通过涉及 PP2A/Akt/Mcl-1 轴的过程，使 RCC 细胞对 ABT-737 恢复了敏感性。
