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

// Hsin-Hwa Tsai 1, * , Hong-Yue Lai 2, * , Yueh-Chiu Chen 3, * , Chien-Feng Li 4 , Huei-Sheng Huang 5 , Hsiao-Sheng Liu 6 , Yau-Sheng Tsai 7 , Ju-Ming Wang 1, 8 1 Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan 2 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan 3 Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan 4 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 5 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan 6 Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan 7 Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan 8 Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan * The authors contributed equally to this work Correspondence to: Ju-Ming Wang, email: yumingw@mail.ncku.edu.tw 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.