Wuxi School of Medicine, Jiangnan University, Wuxi, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Sci Rep. 2017 Jun 9;7(1):3158. doi: 10.1038/s41598-017-03230-w.
Adriamycin is a first-line chemotherapy agent against cancer, but the development of resistance has become a major problem. Although autophagy is considered to be an adaptive survival response in response to chemotherapy and may be associated with chemoresistance, its inducer and the underlying molecular mechanisms remain unclear. Here, we demonstrate that adriamycin up-regulates the both levels of TRPC5 and autophagy, and the increase in autophagy is mediated by TRPC5 in breast cancer cells. Blockade of TRPC5 or autophagy increased the sensitivity to chemotherapy in vitro and in vivo. Notably, we revealed a positive correlation between TRPC5 and the autophagy-associated protein LC3 in paired patients with or without anthracycline-taxane-based chemotherapy. Furthermore, pharmacological inhibition and gene-silencing showed that the cytoprotective autophagy mediated by TRPC5 during adriamycin treatment is dependent on the CaMKKβ/AMPKα/mTOR pathway. Moreover, adriamycin-resistant MCF-7/ADM cells maintained a high basal level of autophagy, and silencing of TRPC5 and inhibition of autophagy counteracted the resistance to adriamycin. Thus, our results revealed a novel role of TRPC5 as an inducer of autophagy, and this suggests a novel mechanism of drug resistance in chemotherapy for breast cancer.
阿霉素是一种针对癌症的一线化疗药物，但耐药性的发展已成为一个主要问题。尽管自噬被认为是对化疗的一种适应性生存反应，并且可能与化疗耐药性有关，但自噬的诱导剂及其潜在的分子机制仍不清楚。在这里，我们证明阿霉素上调了 TRPC5 和自噬的水平，并且自噬的增加是由乳腺癌细胞中的 TRPC5 介导的。阻断 TRPC5 或自噬会增加体外和体内对化疗的敏感性。值得注意的是，我们在接受或不接受蒽环类药物-紫杉烷类化疗的配对患者中发现了 TRPC5 与自噬相关蛋白 LC3 之间的正相关。此外，药理学抑制和基因沉默表明，在阿霉素治疗期间，TRPC5 介导的细胞保护自噬依赖于 CaMKKβ/AMPKα/mTOR 通路。此外，阿霉素耐药 MCF-7/ADM 细胞维持高水平的基础自噬，沉默 TRPC5 和抑制自噬可逆转对阿霉素的耐药性。因此，我们的结果揭示了 TRPC5 作为自噬诱导剂的新作用，并提示了乳腺癌化疗耐药的新机制。
