title: Dehydroepiandrosterone-induced changes in mitochondrial proteins contribute to phenotypic alterations in hepatoma cells.
abstract: Dehydroepiandrosterone (DHEA)-induced growth arrest of hepatoma cells is associated with metabolic disturbance. Our previous study has suggested that DHEA may cause cellular energy drain. It is possible that mitochondrial dysfunction may be mechanistically implicated in DHEA-induced changes in cellular phenotype. Treatment of SK-Hep-1 cells with DHEA caused significant reduction in proliferation, colony formation, and growth in semi-solid medium. Such changes in cellular phenotype were associated with mitochondrial depolarization, increase in mitochondrial mass, and decrease in respiratory activity. Level of reactive oxygen species (ROS) increased in DHEA-treated cells. To explore the mechanistic aspect of DHEA-induced mitochondrial dysfunction, we employed SILAC approach to study the changes in the mitoproteome of SK-Hep-1 cells after DHEA treatment. Respiratory chain complex proteins such as NDUFB8 and SDHB were differentially expressed. Of mitochondrial proteins with altered expression, FAST kinase domain-containing protein 2 (FASTKD2) showed significantly reduced expression. Exogenous expression of FASTKD2 in SK-Hep-1 cells increased their resistance to growth-inhibitory effect of DHEA, though it alone did not affect cell growth. FASTKD2 expression partially reversed the effect of DHEA on mitochondria, and reduced DHEA-induced ROS generation. Our results suggest that DHEA induces changes in mitochondrial proteins and respiratory activity, and contributes to growth arrest. FASTKD2 may be an important regulator of mitochondrial physiology, and represent a downstream target for DHEA.
authors: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan; Metabolomics Core Laboratory, Chang Gung University, Tao-Yuan, Taiwan; Clinical Phenome Center, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan.
authors: Mei-Ling
authors: ML
authors: Cheng
authors: Clinical Proteomics Core Laboratory, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan.
authors: Lang-Ming
authors: LM
authors: Chi
authors: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors: Pei-Ru
authors: PR
authors: Wu
authors: Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan; Clinical Phenome Center, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address: hoh01@mail.cgu.edu.tw.
authors: Hung-Yao
authors: HY
authors: Ho
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D024101:Mitochondrial Proteins; C000618340:NDUFB8 protein, human; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D003687:Dehydroepiandrosterone; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; C532222:FASTKD2 protein, human; D017346:Protein Serine-Threonine Kinases; D042967:Electron Transport Complex I
keywords: DHEA; FASTKD2; Mitochondria; Proteomics