title: Therapeutic strategies impacting cancer cell glutamine metabolism.
abstract: The metabolic adaptations that support oncogenic growth can also render cancer cells dependent on certain nutrients. Along with the Warburg effect, increased utilization of glutamine is one of the metabolic hallmarks of the transformed state. Glutamine catabolism is positively regulated by multiple oncogenic signals, including those transmitted by the Rho family of GTPases and by c-Myc. The recent identification of mechanistically distinct inhibitors of glutaminase, which can selectively block cellular transformation, has revived interest in the possibility of targeting glutamine metabolism in cancer therapy. Here, we outline the regulation and roles of glutamine metabolism within cancer cells and discuss possible strategies for, and the consequences of, impacting these processes therapeutically.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, NY 14850-6401, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lukey
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Wilson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005973:Glutamine; D005972:Glutaminase
references.citation: Neurochem Int. 2009 Jul-Aug;55(1-3):71-5
references.pmid: 19428809
references.citation: Biochem J. 2007 Sep 15;406(3):407-14
references.pmid: 17581113
references.citation: Neuropsychopharmacology. 2009 Sep;34(10):2305-22
references.pmid: 19516252
references.citation: Cancer Res. 1994 Apr 1;54(7):1690-4
references.pmid: 8137283
references.citation: J Cereb Blood Flow Metab. 2012 May;32(5):816-24
references.pmid: 22373647
references.citation: Cancer Cell. 2012 Nov 13;22(5):631-44
references.pmid: 23153536
references.citation: Oncogene. 2010 Jan 21;29(3):313-24
references.pmid: 19881548
references.citation: Cell Cycle. 2010 Oct 1;9(19):3884-6
references.pmid: 20948290
references.citation: Nutrition. 2002 Mar;18(3):217-21
references.pmid: 11882392
references.citation: Nat Biotechnol. 2012 Jul 10;30(7):671-8
references.pmid: 22781696
references.citation: Annu Rev Nutr. 1995;15:133-59
references.pmid: 8527215
references.citation: Oncogene. 2014 Jan 30;33(5):556-66
references.pmid: 23353822
references.citation: Cancer Cell. 2010 Sep 14;18(3):207-19
references.pmid: 20832749
references.citation: Cancer Res. 2009 Oct 15;69(20):7986-93
references.pmid: 19826036
references.citation: J Biol Chem. 2009 Nov 20;284(47):32742-9
references.pmid: 19783659
references.citation: Bioorg Med Chem. 2005 Feb 15;13(4):1111-8
references.pmid: 15670919
references.citation: J Nucl Med. 2011 Jul;52(7):1005-8
references.pmid: 21680688
references.citation: J Cell Biochem. 1993 Dec;53(4):343-51
references.pmid: 7905486
references.citation: Circ Res. 2010 Jul 23;107(2):171-85
references.pmid: 20651294
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21069-74
references.pmid: 22106309
references.citation: Nature. 2011 Nov 20;481(7381):380-4
references.pmid: 22101433
references.citation: Clin Exp Immunol. 1999 Sep;117(3):482-8
references.pmid: 10469051
references.citation: Semin Cell Dev Biol. 2012 Jun;23(4):362-9
references.pmid: 22349059
references.citation: Mol Cell Biochem. 1995 Nov 22;152(2):95-101
references.pmid: 8751155
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Blood. 2000 Sep 1;96(5):1709-15
references.pmid: 10961868
references.citation: Cancer Chemother Pharmacol. 2011 Feb;67(2):285-91
references.pmid: 20383709
references.citation: Pharmacol Ther. 1990;46(2):243-71
references.pmid: 2108451
references.citation: Mol Syst Biol. 2011 Aug 16;7:523
references.pmid: 21847114
references.citation: J Nutr. 2008 Feb;138(2):338-43
references.pmid: 18203901
references.citation: Science. 1955 Sep 16;122(3168):501-14
references.pmid: 13255879
references.citation: Breast Cancer Res. 2008;10(5):R84
references.pmid: 18922152
references.citation: J Nutr. 2001 Sep;131(9 Suppl):2491S-5S; discussion 2496S-7S
references.pmid: 11533299
references.citation: Biochim Biophys Acta. 2012 Jan;1825(1):111-6
references.pmid: 22101401
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
references.pmid: 18032601
references.citation: Cell Metab. 2008 Jan;7(1):11-20
references.pmid: 18177721
references.citation: J Cell Biol. 2007 Jul 2;178(1):93-105
references.pmid: 17606868
references.citation: J Neurosci. 2006 Apr 26;26(17):4660-71
references.pmid: 16641247
references.citation: Neurochem Int. 2006 May-Jun;48(6-7):465-71
references.pmid: 16516349
references.citation: J Nucl Med. 2011 Dec;52(12):1947-55
references.pmid: 22095958
references.citation: Glia. 2009 Jul;57(9):1014-23
references.pmid: 19062176
references.citation: J Cell Biol. 2002 Apr 29;157(3):349-55
references.pmid: 11980913
references.citation: Trends Mol Med. 2013 Feb;19(2):74-82
references.pmid: 23219172
references.citation: Cell Cycle. 2010 Oct 1;9(19):3921-32
references.pmid: 20935507
references.citation: Mamm Genome. 2000 Dec;11(12):1107-10
references.pmid: 11130979
references.citation: Clin Cancer Res. 2012 Aug 15;18(16):4240-6
references.pmid: 22648273
references.citation: J Biol Chem. 1998 Jun 5;273(23):14484-94
references.pmid: 9603962
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Nature. 2009 Dec 10;462(7274):739-44
references.pmid: 19935646
references.citation: Biochem J. 2000 Jan 15;345 Pt 2:365-75
references.pmid: 10620514
references.citation: Adv Enzyme Regul. 1982;20:75-96
references.pmid: 6180609
references.citation: Cell Metab. 2012 Jan 4;15(1):110-21
references.pmid: 22225880
references.citation: Sci Transl Med. 2010 May 12;2(31):31ed1
references.pmid: 20463364
references.citation: Physiol Genomics. 1999 Aug 31;1(2):51-62
references.pmid: 11015561
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93
references.pmid: 20421486
references.citation: Proc Natl Acad Sci U S A. 2011 May 24;108(21):8674-9
references.pmid: 21555572
references.citation: Leukemia. 2004 Mar;18(3):434-41
references.pmid: 14724653
references.citation: Arch Toxicol. 2012 Nov;86(11):1649-65
references.pmid: 22811024
references.citation: Am J Physiol. 1997 May;272(5 Pt 1):G943-53
references.pmid: 9176200
references.citation: J Mol Med (Berl). 2011 Mar;89(3):213-20
references.pmid: 21301796
references.citation: J Biol Chem. 1984 May 25;259(10):6215-21
references.pmid: 6144677
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
references.pmid: 19033189
references.citation: Cell. 2009 Feb 6;136(3):521-34
references.pmid: 19203585
references.citation: Nat Rev Cancer. 2011 Feb;11(2):85-95
references.pmid: 21258394
references.citation: Trends Biochem Sci. 2010 Aug;35(8):427-33
references.pmid: 20570523
references.citation: Genes Dev. 2010 Dec 15;24(24):2784-99
references.pmid: 21106670
references.citation: FEBS J. 2011 Aug;278(15):2739-50
references.pmid: 21696544
references.citation: Crit Rev Clin Lab Sci. 2006;43(2):143-81
references.pmid: 16517421
references.citation: Nat Rev Drug Discov. 2011 Oct 31;10(11):868-80
references.pmid: 22037041
references.citation: Physiol Genomics. 2002;9(3):157-66
references.pmid: 12045296
references.citation: Curr Mol Med. 2013 May;13(4):514-34
references.pmid: 22934847
references.citation: J Am Chem Soc. 2011 Feb 2;133(4):1122-33
references.pmid: 21190335
references.citation: In Vivo. 2004 Mar-Apr;18(2):107-12
references.pmid: 15113036
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7461-6
references.pmid: 20351271
references.citation: J Proteomics. 2013 Mar 27;80:236-49
references.pmid: 23376484
references.citation: Nature. 2011 Nov 20;481(7381):385-8
references.pmid: 22101431
references.citation: J Med Chem. 2012 Dec 13;55(23):10551-63
references.pmid: 23151085
references.citation: Mol Cancer Ther. 2012 Jun;11(6):1269-78
references.pmid: 22496480
references.citation: J Cell Physiol. 2008 Jun;215(3):593-602
references.pmid: 18181196
references.citation: J Nucl Med. 2012 Jan;53(1):98-105
references.pmid: 22173839
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Mar;286(3):G467-78
references.pmid: 14563674
references.citation: Nat Rev Drug Discov. 2011 Aug 31;10(9):671-84
references.pmid: 21878982
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1092-7
references.pmid: 22228304
references.citation: Pigment Cell Melanoma Res. 2012 May;25(3):375-83
references.pmid: 22360810
references.citation: Clin Cancer Res. 2013 Feb 1;19(3):560-70
references.pmid: 23213057
references.citation: J Cell Biol. 1991 Nov;115(4):887-903
references.pmid: 1955461
references.citation: J Nutr. 2001 Sep;131(9 Suppl):2515S-22S; discussion 2523S-4S
references.pmid: 11533304
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Dec;293(6):G1262-71
references.pmid: 17916648
references.citation: Am J Physiol. 1998 May;274(5):E801-7
references.pmid: 9612237
references.citation: Sci Transl Med. 2010 May 12;2(31):31ra34
references.pmid: 20463368
references.citation: Nature. 2013 Apr 4;496(7443):101-5
references.pmid: 23535601
references.citation: Int J Biochem. 1993 Dec;25(12):1749-55
references.pmid: 8138012
references.citation: Cell Metab. 2013 Mar 5;17(3):372-85
references.pmid: 23473032
references.citation: Clin Pharmacokinet. 2005;44(4):367-93
references.pmid: 15828851
references.citation: J Biol Chem. 2011 Jun 24;286(25):22323-30
references.pmid: 21540181
references.citation: Hippocampus. 2012 May;22(5):1027-39
references.pmid: 22431402
references.citation: Cancer Res. 2010 Nov 15;70(22):8981-7
references.pmid: 21045145
references.citation: Science. 1956 Aug 10;124(3215):269-70
references.pmid: 13351639
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7455-60
references.pmid: 20378837
references.citation: PLoS One. 2009;4(3):e4715
references.pmid: 19262748
references.citation: Semin Oncol. 2011 Feb;38(1):55-69
references.pmid: 21362516
references.citation: Sci Signal. 2010 Apr 27;3(119):ra31
references.pmid: 20424262
references.citation: Epigenetics. 2012 Dec 1;7(12):1413-20
references.pmid: 23117580
references.citation: Semin Cancer Biol. 2005 Aug;15(4):254-66
references.pmid: 15916903
references.citation: Biochemistry. 2011 Dec 20;50(50):10764-70
references.pmid: 22049910
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19611-6
references.pmid: 22106302
references.citation: Mol Cancer. 2011 Feb 14;10:19
references.pmid: 21320304
references.citation: J Invest Dermatol. 2010 Sep;130(9):2240-9
references.pmid: 20505744
references.citation: J Enzyme Inhib Med Chem. 2012 Dec;27(6):861-7
references.pmid: 21999665
references.citation: Proc Natl Acad Sci U S A. 2012 May 15;109(20):7705-10
references.pmid: 22538822
references.citation: J Immunol. 2010 Jul 15;185(2):1037-44
references.pmid: 20554958
references.citation: Nature. 2009 Apr 9;458(7239):762-5
references.pmid: 19219026
references.citation: Nat Cell Biol. 2012 Aug;14(8):829-37
references.pmid: 22820375
references.citation: Am J Physiol Cell Physiol. 2007 Jul;293(1):C55-63
references.pmid: 17329400
references.citation: Adv Enzyme Regul. 1976;14:25-42
references.pmid: 184697
references.citation: J Cell Biochem. 2008 Feb 15;103(3):800-11
references.pmid: 17614351
references.citation: Cell. 2012 Sep 14;150(6):1196-208
references.pmid: 22980980
references.citation: In Vivo. 2006 Sep-Oct;20(5):587-9
references.pmid: 17091764
references.citation: Mol Cell. 2012 Aug 10;47(3):349-58
references.pmid: 22749528
references.citation: Genes Dev. 2010 Dec 15;24(24):2717-22
references.pmid: 21159812
references.citation: Autophagy. 2012 Jan;8(1):122-3
references.pmid: 22170154
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683