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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ashby MN . CaaX converting enzymes. Curr Opin Lipidol 1998; 9: 99–102.
Winter-Vann AM, Casey PJ . Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 2005; 5: 405–412.
Seabra MC . Membrane association and targeting of prenylated Ras-like GTPases. Cell Signal 1998; 10: 167–172.
Bergo MO, Leung GK, Ambroziak P, Otto JC, Casey PJ, Young SG . Targeted inactivation of the isoprenylcysteine carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells. J Biol Chem 2000; 275: 17605–17610.
Cushman I, Casey PJ . RHO methylation matters: a role for isoprenylcysteine carboxylmethyltransferase in cell migration and adhesion. Cell Adhes Migr 2011; 5: 11–15.
Wahlstrom AM, Cutts BA, Liu M, Lindskog A, Karlsson C, Sjogren AK et al. Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease. Blood 2008; 112: 1357–1365.
Bergo MO, Gavino BJ, Hong C, Beigneux AP, McMahon M, Casey PJ et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J Clin Invest 2004; 113: 539–550.
Wang M, Tan W, Zhou J, Leow J, Go M, Lee HS et al. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J Biol Chem 2008; 283: 18678–18684.
Wang M, Hossain MS, Tan W, Coolman B, Zhou J, Liu S et al. Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene 2010; 29: 4959–4970.
Mihaylova MM, Shaw RJ . The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011; 13: 1016–1023.
Kim J, Kundu M, Viollet B, Guan KL . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132–141.
Krebs HA, Hems R . Phosphate-transfer reactions of adenosine and inosine nucleotides. Biochem J 1955; 61: 435–441.
Berg P, Joklik WK . Transphosphorylation between nucleoside polyphosphates. Nature 1953; 172: 1008–1009.
Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD et al. A protein conjugation system essential for autophagy. Nature 1998; 395: 395–398.
Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y . The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 2001; 20: 5971–5981.
Barrientos A . In vivo and in organello assessment of OXPHOS activities. Methods 2002; 26: 307–316.
Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13: 376–388.
Inoki K, Zhu T, Guan KL . TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577–590.
Carling D, Zammit VA, Hardie DG . A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 1987; 223: 217–222.
Sato R, Goldstein JL, Brown MS . Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc Natl Acad Sci USA 1993; 90: 9261–9265.
Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 1997; 272: 26457–26463.
Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999; 13: 1422–1437.
Winter-Vann AM, Baron RA, Wong W, dela Cruz J, York JD, Gooden DM et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc Natl Acad Sci USA 2005; 102: 4336–4341.
Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D . RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 2011; 11: 761–774.
King MP, Attardi G . Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 1989; 246: 500–503.
Chandel NS, Schumacker PT . Cells depleted of mitochondrial DNA (rho0) yield insight into physiological mechanisms. FEBS Lett 1999; 454: 173–176.
Potter VR . The biochemical approach to the cancer problem. Fed Proc 1958; 17: 691–697.
King MP, Attardi G . Isolation of human cell lines lacking mitochondrial DNA. Methods Enzymol 1996; 264: 304–313.
Vander Heiden MG, Cantley LC, Thompson CB . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–1033.
Gregoire M, Morais R, Quilliam MA, Gravel D . On auxotrophy for pyrimidines of respiration-deficient chick embryo cells. Eur J Biochem/FEBS 1984; 142: 49–55.
Neuzil J, Dong LF, Ramanathapuram L, Hahn T, Chladova M, Wang XF et al. Vitamin E analogues as a novel group of mitocans: anti-cancer agents that act by targeting mitochondria. Mol Aspects Med 2007; 28 (5-6): 607–645.
Pathania D, Millard M, Neamati N . Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev 2009; 61: 1250–1275.
Zhu WL, Hossain MS, Guo DY, Liu S, Tong H, Khakpoor A et al. A role for Rac3 GTPase in the regulation of autophagy. J Biol Chem 2011; 286: 35291–35298.
Cordell RL, Hill SJ, Ortori CA, Barrett DA . Quantitative profiling of nucleotides and related phosphate-containing metabolites in cultured mammalian cells by liquid chromatography tandem electrospray mass spectrometry. J Chromatogr B 2008; 871: 115–124.
Wu JY, Kao HJ, Li SC, Stevens R, Hillman S, Millington D et al. ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease. J Clin Invest 2004; 113: 434–440.
An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 2004; 10: 268–274.
Millington DS, Terada N, Chace DH, Chen YT, Ding JH, Kodo N et al. The role of tandem mass spectrometry in the diagnosis of fatty acid oxidation disorders. Progr Clin Biol Res 1992; 375: 339–354.
Millington DS, Stevens RD . Acylcarnitines: analysis in plasma and whole blood using tandem mass spectrometry. Methods Mol Biol 2011; 708: 55–72.
Chace DH, Millington DS, Terada N, Kahler SG, Roe CR, Hofman LF . Rapid diagnosis of phenylketonuria by quantitative analysis for phenylalanine and tyrosine in neonatal blood spots by tandem mass spectrometry. Clin Chem 1993; 39: 66–71.
Jensen MV, Joseph JW, Ilkayeva O, Burgess S, Lu D, Ronnebaum SM et al. Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J Biol Chem 2006; 281: 22342–22351.
Acknowledgements
These experiments were supported by grant from National Medical Research Council (NMRC) and Duke-NUS institutional funding. Wild-type and Icmt-null MEFs are from Dr M Bergo.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Teh, J., Zhu, W., Ilkayeva, O. et al. Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism. Oncogene 34, 3296–3304 (2015). https://doi.org/10.1038/onc.2014.260
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2014.260
This article is cited by
-
An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review
Molecular Diversity (2024)
-
RAB4A GTPase regulates epithelial-to-mesenchymal transition by modulating RAC1 activation
Breast Cancer Research (2022)
-
Isoprenylcysteine carboxyl methyltransferase is critical for glioblastoma growth and survival by activating Ras/Raf/Mek/Erk
Cancer Chemotherapy and Pharmacology (2022)
-
Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal
Oncogene (2020)
-
Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms
Oncogene (2017)