Authors' Affiliation: Departments of Pharmacology and Biomedical Science, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Cancer Res. 2014 Jan 1;74(1):298-308. doi: 10.1158/0008-5472.CAN-13-2620. Epub 2013 Nov 15.
SIRT1 is an NAD(+)-dependent protein deacetylase induced by metabolic stresses, such as nutrition or oxygen deprivation. Although SIRT1 contributes to aging and metabolic disorders, its role in cancer progression and therapeutic responses remains controversial. Because hypoxia occurs widely in solid tumors, where it provokes drug resistance, we investigated the involvement of SIRT1 in hypoxia-induced chemoresistance. SIRT1 was downregulated in a panel of non-small cell lung carcinoma (NSCLC) cells exposed to hypoxia for 48 hours. The master metabolic kinase AMP-activated protein kinase (AMPK) was inactivated under the same conditions, likely due to attenuation of the SIRT1/LKB1-mediated AMPK activation process. Notably, hypoxic inactivation of this SIRT1-AMPK pathway led to cisplatin and doxorubicin resistance. Mechanistic investigations suggested that this pathway supported the cytotoxic response to cisplatin and doxorubicin by licensing an apoptotic process controlled by mitochondria. We confirmed the involvement of this pathway in a mouse xenograft model of human NSCLC. Furthermore, we demonstrated that a SIRT1 activator SRT1720 augmented the antitumor effects of cisplatin, and these effects could be blocked by administration of an AMPK inhibitor compound C. Taken together, our results offer preclinical proof-of-concept to target the SIRT1-AMPK pathway as a strategy to overcome hypoxia-induced chemoresistance in NSCLC.
SIRT1 是一种 NAD(+) 依赖的蛋白去乙酰化酶，可被代谢应激诱导，如营养或缺氧。尽管 SIRT1 参与衰老和代谢紊乱，但它在癌症进展和治疗反应中的作用仍存在争议。由于缺氧广泛存在于实体肿瘤中，会引发耐药性，我们研究了 SIRT1 在缺氧诱导的化疗耐药中的作用。在一组非小细胞肺癌 (NSCLC) 细胞中，暴露于缺氧 48 小时后 SIRT1 下调。在相同条件下，主代谢激酶 AMP 激活蛋白激酶 (AMPK) 失活，可能是由于 SIRT1/LKB1 介导的 AMPK 激活过程减弱。值得注意的是，该 SIRT1-AMPK 通路的缺氧失活导致顺铂和阿霉素耐药。机制研究表明，该通路通过许可由线粒体控制的细胞凋亡过程来支持顺铂和阿霉素的细胞毒性反应。我们在人类 NSCLC 的小鼠异种移植模型中证实了该通路的参与。此外，我们证明了 SIRT1 激活剂 SRT1720 增强了顺铂的抗肿瘤作用，并且这些作用可以通过给予 AMPK 抑制剂化合物 C 来阻断。总之，我们的研究结果为靶向 SIRT1-AMPK 通路作为克服 NSCLC 中缺氧诱导的化疗耐药的策略提供了临床前概念验证。
