Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis
Hong Wu1,2,3, Tao Wang4, Yiqiang Liu2,3
1Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, 518055, Shenzhen, China.
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:
Hypoxia 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.
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 showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice.
Conclusions:
Loss 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.
Insights
Loss of ATAD3A gene activates mitophagy, driving sorafenib resistance in hepatocellular carcinoma (HCC). Targeting the miR-210-5P-ATAD3A pathway may restore drug sensitivity in HCC patients.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Hepatocellular carcinoma (HCC) patients require novel strategies to overcome sorafenib resistance.
- Mitophagy, the selective degradation of mitochondria, is implicated in cancer drug resistance.
- Identifying key regulators of mitophagy is crucial for developing new HCC treatments.
Purpose of the Study:
- To investigate the role of mitophagy in sorafenib resistance in HCC.
- To identify the core regulator of mitophagy involved in HCC drug resistance.
- To explore the potential of targeting mitophagy regulators for HCC therapy.
Main Methods:
- Establishing hypoxia-induced sorafenib-resistant HCC cells.
- Utilizing RNA sequencing and lentivirus-mediated gene manipulation (sh-ATAD3A).
- Conducting in vitro mechanistic studies and in vivo xenograft assays with sorafenib and miR-210-5P antagomir.
Main Results:
- Hyperactivated mitophagy, regulated by the ATAD3A-PINK1/PARKIN axis, was observed in resistant HCC cells.
- ATAD3A downregulation correlated with increased mitophagy and sorafenib resistance.
- ATAD3A was identified as a target of miR-210-5p, which was upregulated under hypoxia and contributed to resistance.
Conclusions:
- Loss of ATAD3A leads to mitophagy activation, a key event in hypoxia-induced sorafenib resistance in HCC.
- The miR-210-5P-ATAD3A axis represents a novel therapeutic target for sorafenib-resistant HCC.
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