期刊
ONCOTARGET
卷 8, 期 8, 页码 13832-13845出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14640
关键词
HCC; autophagy; apoptosis; CEBPD; metformin
资金
- Ministry of Science and Technology [MOST 105-2321B-006-029, MOST 103-2320-B-006-034-MY3]
- Liver Disease Prevention & Treatment Research Foundation, Taiwan from National Health Research Institutes [NHRI-EX105-10422BI]
Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPD-regulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin- induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC.
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