Abstract
BackgroundThe 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.MethodsHypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O2 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.ResultsWe 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 showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice.ConclusionsLoss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC.
Highlights
The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients
Hyperactivated mitophagy plays a vital role in hypoxiainduced sorafenib resistance As shown in Supplementary Fig. S1a-1d, HCC cells cultured under hypoxia showed significantly lower apoptosis rates and better cell viability response to sorafenib treatment in a time-dependent manner
TCGA analysis results showed that PTEN–induced putative kinase protein 1 (PINK1) levels were positively correlated with that of ATP-binding cassette subfamily B member 1 (ABCB1) and ABCG2 in HCC patients (Fig. 1g-h), and Hypoxia-inducible factor 1α (HIF-1α) was positively correlated with Multidrug resistance-associated protein 1 (ABCC1) and negatively with Mitochondrial import receptor subunit TOM20 homolog (TOMM20) and Mitochondrial import receptor subunit TOM70 homolog (TOMM70) (Supplementary Fig. S1f-1 h)
Summary
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. 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. Several mitophagic pathways have been identified that counteract therapy-induced mitochondrial damage [5, 6]. The predominance of certain mitophagy receptors or mediators in specific cancer subtypes is a decisive factor in therapeutic resistance via mitochondrial clearance [6, 12], and the underlying mechanisms are still unclear
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