title: Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism.
abstract: Isoprenylcysteine carboxylmethyltransferase (Icmt) catalyzes the last of the three-step posttranslational protein prenylation process for the so-called CaaX proteins, which includes many signaling proteins, such as most small GTPases. Despite extensive studies on Icmt and its regulation of cell functions, the mechanisms of much of the impact of Icmt on cellular functions remain unclear. Our recent studies demonstrated that suppression of Icmt results in induction of autophagy, inhibition of cell growth and inhibition of proliferation in various cancer cell types, prompting this investigation of potential metabolic regulation by Icmt. We report here the findings that Icmt inhibition reduces the function of mitochondrial oxidative phosphorylation in multiple cancer cell lines. In-depth oximetry analysis demonstrated that functions of mitochondrial complex I, II and III are subject to Icmt regulation. Consistently, Icmt inhibition decreased cellular ATP and depleted critical tricarboxylic acid cycle metabolites, leading to suppression of cell anabolism and growth, and marked autophagy. Several different approaches demonstrated that the impact of Icmt inhibition on cell proliferation and viability was largely mediated by its effect on mitochondrial respiration. This previously unappreciated function of Icmt, which can be therapeutically exploited, likely has a significant role in the impact of Icmt on tumorigenic processes.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: J T
authors.initials: JT
authors.lastname: Teh
authors.affiliation: 1] Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore [2] Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: W L
authors.initials: WL
authors.lastname: Zhu
authors.affiliation: Sarah W Stedman Nutrition and Metabolism Center, and Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: O R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Sarah W Stedman Nutrition and Metabolism Center, and Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gooding
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: P J
authors.initials: PJ
authors.lastname: Casey
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: S A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: Sarah W Stedman Nutrition and Metabolism Center, and Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: 1] Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore [2] Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; C530692:cysmethynil; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D055372:AMP-Activated Protein Kinases