MOTS-c relieves hepatocellular carcinoma resistance to TRAIL-induced apoptosis under hypoxic conditions by activating MEF2A
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Haiying Shen1, Junjie Nie2, Xiaojun Wang3
1Department of Pathophysiology, School of Basic Medicine, Jilin Medical University, Jilin 132013, Jilin Province, PR China.
Background:
Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) as an AMPK agonist can regulate the expression of adaptive nuclear genes to promote cell homeostasis. However, the investigation of MOTS-c in hepatocellular carcinoma (HCC) is insufficient. This study aims to reveal the role of MOTS-c on HCC cell apoptosis.
Methods:
Huh7 and HCCLM3 cells were incubated with MOTS-c under a hypoxic condition. MOTS-c levels were quantified by enzyme-linked immunosorbent assay in the peripheral blood of HCC patients and healthy controls. Cell viability was detected by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was investigated by flow cytometry and Tunel assay. Protein expression was detected by western blotting or immunohistochemistry assay. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to identify the association among myocyte enhancer factor 2A (MEF2A), death receptor 4 (DR4) and DR5. A tumor-bearing nude mouse model was conducted to assess the effect of MOTS-c on HCC tumor formation in vivo.
Results:
MOTS-c levels in the peripheral blood of HCC patients were significantly lower compared to healthy individuals. MOTS-c promoted HCC cell apoptosis under hypoxia conditions. Hypoxia stimulation decreased the protein expression of MEF2A, DR4, DR5, fas-associating via death domain (FADD) and caspase-8, while these effects were attenuated after MOTS-c treatment. MOTS-c induced TRAIL-induced apoptosis of HCC cells by activating MEF2A through the phosphorylation of AMPK under hypoxia treatment. In addition, MEF2A transcriptionally up-regulated DR4 and DR5. MOTS-c activated MEF2A to regulate DR4 and DR5 expression, further mediating TRAIL-induced apoptosis. Further, MOTS-c treatment relieved hypoxia-induced tumor growth in vivo.
Conclusion:
MOTS-c relieved hypoxia-induced HCC cell resistance to TRAIL-caused apoptosis by activating MEF2A.
Insights
Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) combats hepatocellular carcinoma (HCC) by enhancing apoptosis. This study shows MOTS-c activates MEF2A, increasing sensitivity to TRAIL-induced cell death, even under hypoxia.
Area of Science:
- Cellular and Molecular Biology
- Cancer Research
- Mitochondrial Biology
Background:
- Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is an AMPK agonist that regulates nuclear gene expression for cell homeostasis.
- Its role in hepatocellular carcinoma (HCC) remains under-investigated.
- This study explores MOTS-c's function in promoting HCC cell apoptosis.
Purpose of the Study:
- To investigate the role of MOTS-c in hepatocellular carcinoma (HCC) cell apoptosis.
- To determine the molecular mechanisms by which MOTS-c influences HCC cell survival under hypoxic conditions.
- To assess the therapeutic potential of MOTS-c in a preclinical HCC model.
Main Methods:
- Quantified MOTS-c levels in HCC patients and healthy controls via ELISA.
- Assessed HCC cell viability, apoptosis (flow cytometry, Tunel assay), and protein expression (western blotting, immunohistochemistry) under hypoxia with MOTS-c treatment.
- Utilized dual-luciferase reporter and chromatin immunoprecipitation assays to examine MEF2A, DR4, and DR5 interactions.
- Evaluated MOTS-c's effect on HCC tumor growth in a nude mouse model.
Main Results:
- Lower MOTS-c levels were observed in HCC patients compared to healthy controls.
- MOTS-c treatment promoted HCC cell apoptosis under hypoxia.
- MOTS-c activated MEF2A through AMPK phosphorylation, up-regulating DR4 and DR5 expression and enhancing TRAIL-induced apoptosis.
- MOTS-c treatment reduced tumor growth in vivo.
Conclusions:
- MOTS-c overcomes hypoxia-induced resistance to TRAIL-induced apoptosis in HCC cells.
- Activation of MEF2A by MOTS-c is a key mechanism mediating this anti-cancer effect.
- MOTS-c demonstrates potential as a therapeutic agent for HCC.
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