title: The mitochondrial carrier SLC25A10 regulates cancer cell growth.
abstract: Dysregulation of cell metabolism is critical for the growth properties of cancer cells. The purpose of this study was to understand the role of substrate transport across the mitochondrial membrane to sustain the metabolic shift and redox defense in cancer cells. Mitochondrial carrier SLC25A10 is up-regulated in a variety of tumors and is involved in regulating intracellular levels of reactive oxygen species. We show that knockdown of SLC25A10 in A549 cells changed the growth properties to a less malignant phenotype and casued increased glutamine dependency and sensitivity to oxidative stress. The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1α. We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine. The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies.
authors: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors: Xiaoshan
authors: X
authors: Zhou
authors: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors: João A
authors: JA
authors: Paredes
authors: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors: Shuba
authors: S
authors: Krishnan
authors: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors: Sophie
authors: S
authors: Curbo
authors: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors: Anna
authors: A
authors: Karlsson
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism / Q000502:physiology*; D005969:Glutamate Dehydrogenase / Q000096:biosynthesis; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D009249:NADP / Q000096:biosynthesis; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000235:genetics; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D029382:Dicarboxylic Acid Transporters; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000605013:Slc25a10 protein, human; D009249:NADP; D007770:L-Lactate Dehydrogenase; D005969:Glutamate Dehydrogenase; D002945:Cisplatin
keywords: ROS; SLC25A10; oxidative stress; redox homeostasis