Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway

Hsin Hwa Tsai, Hong Yue Lai, Yueh Chiu Chen, Chien Feng Li, Huei Sheng Huang, Hsiao Sheng Liu, Yau Sheng Tsai, Ju Ming Wang

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


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 CEBPDregulated 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.

Original languageEnglish
Pages (from-to)13832-13845
Number of pages14
Issue number8
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology


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