Carnitine transporter CT2 (SLC22A16) is over-expressed in acute myeloid leukemia (AML) and target knockdown reduces growth and viability of AML cells

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• 作者：Yan Wu ; Rose Hurren ; Neil MacLean ; Marcela Gronda ; Yulia Jitkova…
• 关键词：Acute myeloid leukemia ; Fatty acid oxidation ; Carnitine transporters ; CT2 ; Oxidative phosphorylation
• 刊名：Apoptosis
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：20
• 期：8
• 页码：1099-1108
• 全文大小：990 KB
• 参考文献：1.Carracedo A, Cantley LC, Pandolfi PP (2013) Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13:227鈥?32PubMed Central PubMed View Article
  2.Eaton S, Bartlett K, Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320(Pt 2):345鈥?57PubMed Central PubMed
  3.Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q (2010) Role of carnitine in disease. Nutr Metab 7:30View Article
  4.Vaz FM, Wanders RJ (2002) Carnitine biosynthesis in mammals. Biochem J 361:417鈥?29PubMed Central PubMed View Article
  5.Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227鈥?251PubMed View Article
  6.Gong S, Lu X, Xu Y, Swiderski CF, Jordan CT, Moscow JA (2002) Identification of OCT6 as a novel organic cation transporter preferentially expressed in hematopoietic cells and leukemias. Exp Hematol 30:1162鈥?169PubMed View Article
  7.Koepsell H (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 34:413鈥?35PubMed View Article
  8.Tamai I (2013) Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos 34:29鈥?4PubMed View Article
  9.Samudio I, Harmancey R, Fiegl M et al (2010) Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Investig 120:142鈥?56PubMed Central PubMed View Article
  10.Skrede S, Iversen PO (1995) Enhanced oxygen consumption and fatty acid metabolism in rat bone marrow with acute promyelocytic leukaemia. Leuk Res 19:463鈥?67PubMed View Article
  11.Beheshti Zavareh R, Lau KS, Hurren R et al (2008) Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res 68:6688鈥?697PubMed View Article
  12.Schimmer AD, Thomas MP, Hurren R et al (2006) Identification of small molecules that sensitize resistant tumor cells to tumor necrosis factor-family death receptors. Cancer Res 66:2367鈥?375PubMed View Article
  13.Moffat J, Grueneberg DA, Yang X et al (2006) A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124:1283鈥?298PubMed View Article
  14.Xu GW, Ali M, Wood TE et al (2010) The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood 115:2251鈥?259PubMed Central PubMed View Article
  15.Aouida M, Poulin R, Ramotar D (2010) The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5. J Biol Chem 285:6275鈥?284PubMed Central PubMed View Article
  16.Lagadinou ED, Sach A, Callahan K et al (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12:329鈥?41PubMed Central PubMed View Article
  17.Skrtic M, Sriskanthadevan S, Jhas B et al (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20:674鈥?88PubMed Central PubMed View Article
  18.Gustafson B, Ransnas LA (1997) Regulation of carnitine binding to plasma membranes by an ATP-dependent mechanism. Biochem Biophys Res Commun 231:249鈥?53PubMed View Article
  19.Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M (2011) Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta 1807:726鈥?34PubMed View Article
  20.Tirado-Velez JM, Joumady I, Saez-Benito A, Cozar-Castellano I, Perdomo G (2012) Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. PLoS ONE 7:e46484PubMed Central PubMed View Article
  21.Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18:153鈥?61PubMed Central PubMed View Article
  22.Pizer ES, Thupari J, Han WF et al (2000) Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res 60:213鈥?18PubMed
  23.Thupari JN, Pinn ML, Kuhajda FP (2001) Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochemical and biophysical research communications 285:217鈥?23PubMed View Article
  24.Pizer ES, Wood FD, Pasternack GR, Kuhajda FP (1996) Fatty acid synthase (FAS): a target for cytotoxic antimetabolites in HL60 promyelocytic leukemia cells. Cancer Res 56:745鈥?51PubMed
  25.Spaner DE, Lee E, Shi Y et al (2013) PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia. Leukemia 27:1090鈥?099PubMed View Article
  26.Ferre P (2004) The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 53(Suppl 1):S43鈥揝50PubMed View Article
  27.Enomoto A, Wempe MF, Tsuchida H et al (2002) Molecular identification of a novel carnitine transporter specific to human testis. Insights into the mechanism of carnitine recognition. J Biol Chem 277:36262鈥?6271PubMed View Article
  
• 作者单位：Yan Wu (1) (2)
  Rose Hurren (1)
  Neil MacLean (1)
  Marcela Gronda (1)
  Yulia Jitkova (1)
  Mahadeo A. Sukhai (1)
  Mark D. Minden (1) (2)
  Aaron D. Schimmer (1) (2)
  
  1. Princess Margaret Cancer Centre, Ontario Cancer Institute, 610 University Ave, Toronto, ON, M5G 2M9, Canada
  2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Cancer Research
  Cell Biology
  Biochemistry
  Virology
  
• 出版者：Springer Netherlands
• ISSN：1573-675X

文摘

AML (acute myeloid leukemia) cells have a unique reliance on mitochondrial metabolism and fatty acid oxidation (FAO). Thus, blocking FAO is a potential therapeutic strategy to target these malignant cells. In the current study, we assessed plasma membrane carnitine transporters as novel therapeutic targets for AML. We examined the expression of the known plasma membrane carnitine transporters, OCTN1, OCTN2, and CT2 in AML cell lines and primary AML samples and compared expression to normal hematopoietic cells. Of the three carnitine transporters, CT2 demonstrated the greatest differential expression between AML and normal cells. Using shRNA, we knocked down CT2 and demonstrated that target knockdown impaired the function of the transporter. In addition, knockdown of CT2 reduced the growth and viability of AML cells with high expression of CT2 (OCI-AML2 and HL60), but not low expression. CT2 knockdown reduced basal oxygen consumption without a concomitant increase in glycolysis. Thus, CT2 may be a novel target for a subset of AML.