Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

作者：Hong Wu, Tao Wang, Yiqiang Liu, Xin Li, Senlin Xu, Changtao Wu, Hongbo Zou, Mianfu Cao, Guoxiang Jin, Jinyi Lang, Bin Wang, Baohua Liu, Xiaolin Luo, Chuan Xu · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2020 · DOI：10.1186/s13046-020-01768-8 · 被引用次数：91 · 研究领域：Autophagy in Disease and Therapy、Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism

BACKGROUND: The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients. METHODS: with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir. RESULTS: We found a hyperactivated mitophagy regulating by ATAD3A-PINK1/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay sh...