title: Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway.
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.
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsin-Hwa
authors.initials: HH
authors.lastname: Tsai
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hong-Yue
authors.initials: HY
authors.lastname: Lai
authors.affiliation: Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yueh-Chiu
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Huei-Sheng
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; C497252:CEBPD protein, human; D007004:Hypoglycemic Agents; D051743:CCAAT-Enhancer-Binding Protein-delta; D008687:Metformin
keywords: CEBPD; HCC; apoptosis; autophagy; metformin