title: Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs.
abstract: Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide particularly in Asia. Deregulation of cellular energetics was recently included as one of the cancer hallmarks. Compounds that target the mitochondria in cancer cells were proposed to have therapeutic potential. Biguanide drugs which inhibit mitochondrial complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus patients (T2DM) and were recently found to reduce the risk of HCC in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is still unclear. In the present study, we treated four HCC cell lines with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (metformin and phenformin), and found that the HCC cells which had a higher mitochondrial respiration rate were more sensitive to these treatments; whereas the HCC cells which exhibited higher glycolysis were more resistant. When glucose was replaced by galactose in the medium, the altered energy metabolism from glycolysis to mitochondrial respiration in the HCC cells enhanced the cellular sensitivity to mitochondrial inhibitors and biguanides. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanides. In conclusion, our results suggest that increased mitochondrial oxidative metabolism upregulates the sensitivity of HCC to biguanide drugs. Enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a therapeutic strategy for HCC.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Ling-Chia
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Hsia
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C.
authors.forename: Pen-Hui
authors.initials: PH
authors.lastname: Yin
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Tien-Shun
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000008:administration & dosage; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009840:Oligomycins / Q000008:administration & dosage; D010101:Oxygen Consumption / Q000187:drug effects; D010629:Phenformin / Q000008:administration & dosage; D012402:Rotenone / Q000008:administration & dosage
chemical_list: D009840:Oligomycins; D012402:Rotenone; D000255:Adenosine Triphosphate; D008687:Metformin; D010629:Phenformin