Oncotarget

Research Papers:

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 and Ju-Ming Wang _

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Oncotarget. 2017; 8:13832-13845. https://doi.org/10.18632/oncotarget.14640

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Abstract

Hsin-Hwa Tsai1,*, Hong-Yue Lai2,*, Yueh-Chiu Chen3,*, Chien-Feng Li4, Huei-Sheng Huang5, Hsiao-Sheng Liu6, Yau-Sheng Tsai7, Ju-Ming Wang1,8

1Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan

2Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan

3Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan

4Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

5Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan

6Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan

7Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan

8Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

*The authors contributed equally to this work

Correspondence to:

Ju-Ming Wang, email: [email protected]

Keywords: HCC, autophagy, apoptosis, CEBPD, metformin

Received: May 30, 2016     Accepted: January 04, 2017     Published: January 13, 2017

ABSTRACT

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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