title: Disrupting proton dynamics and energy metabolism for cancer therapy.
abstract: Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.
authors: Institute for Research on Cancer and Aging of Nice (IRCAN), Equipe Labellisée LNCC, University of Nice-Sophia Antipolis, Centre National de la Recherche Scientifique, INSERM, Centre A. Lacassagne, Nice 06189, France.
authors: Scott K
authors: SK
authors: Parks
authors: Johanna
authors: J
authors: Chiche
authors: Jacques
authors: J
authors: Pouysségur
mesh_terms: D001343:Autophagy; D001639:Bicarbonates / Q000378:metabolism; D002255:Carbonic Acid / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011522:Protons; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D059016:Tumor Microenvironment; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D001639:Bicarbonates; D002255:Carbonic Acid; D002256:Carbonic Anhydrases; D027682:Cation Transport Proteins; D051793:Hypoxia-Inducible Factor 1; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D011522:Protons; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human; C490998:SLC9A1 protein, human
references: Cancer Res. 2006 May 15;66(10):5216-23
references: 16707446
references: Mol Pharmacol. 2006 Dec;70(6):2108-15
references: 17000864
references: Pflugers Arch. 2004 Feb;447(5):710-21
references: 12759755
references: Mol Cell. 2012 Dec 14;48(5):681-91
references: 23103253
references: World J Urol. 2011 Feb;29(1):121-6
references: 20512580
references: J Biol Chem. 2011 Aug 5;286(31):27781-91
references: 21680735
references: Cancer Res. 1989 Dec 1;49(23):6449-65
references: 2684393
references: J Biol Chem. 2001 Jun 29;276(26):23849-57
references: 11274162
references: J Gen Physiol. 1927 Mar 7;8(6):519-30
references: 19872213
references: Cancer Res. 2013 Jan 1;73(1):3-7
references: 23288916
references: J Biol Chem. 2009 Jul 24;284(30):20299-310
references: 19458084
references: Cancer Res. 1989 Aug 15;49(16):4477-82
references: 2743336
references: Philos Trans R Soc Lond B Biol Sci. 1982 Dec 1;299(1097):383-99
references: 6130537
references: Biochem Biophys Res Commun. 1993 Oct 29;196(2):699-706
references: 8240346
references: Physiol Rev. 1997 Jan;77(1):51-74
references: 9016300
references: J Biol Chem. 2001 Dec 21;276(51):47886-94
references: 11606574
references: Bioorg Med Chem Lett. 2009 Aug 1;19(15):4102-6
references: 19527930
references: Nature. 2003 Sep 4;425(6953):93-8
references: 12955148
references: Sci Transl Med. 2011 Aug 3;3(94):94ra70
references: 21813754
references: Cancer Cell. 2013 Mar 18;23(3):263-4
references: 23518341
references: Nat Rev Mol Cell Biol. 2007 Nov;8(11):917-29
references: 17912264
references: Curr Opin Genet Dev. 2011 Feb;21(1):67-72
references: 21074987
references: Neuro Oncol. 2012 Nov;14(11):1357-66
references: 23074198
references: Biochem Pharmacol. 1999 May 1;57(9):1037-46
references: 10796074
references: Nat Rev Cancer. 2005 Oct;5(10):786-95
references: 16175178
references: Cancer Res. 2009 Mar 15;69(6):2677-84
references: 19276380
references: Cancer Res. 1980 Jun;40(6):1830-5
references: 7371014
references: Cancer Lett. 2012 Apr 28;317(2):172-83
references: 22120673
references: Cell Death Dis. 2010 Oct 21;1:e87
references: 21368860
references: J Med Chem. 2011 Oct 13;54(19):6905-18
references: 21851094
references: Nature. 2012 Nov 15;491(7424):364-73
references: 23151579
references: Cancer Res. 1996 Dec 15;56(24):5745-53
references: 8971186
references: Cancer Res. 1987 Mar 15;47(6):1497-504
references: 3815351
references: Cancer Res. 2013 Mar 1;73(5):1524-35
references: 23288510
references: Annu Rev Cell Dev Biol. 2011;27:441-64
references: 21985671
references: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
references: 7539918
references: PLoS One. 2011;6(12):e28851
references: 22216126
references: Nature. 1985 Jul 18-24;316(6025):234-8
references: 2410791
references: Mol Cancer Ther. 2002 Jun;1(8):617-28
references: 12479222
references: Nat Rev Cancer. 2004 Nov;4(11):891-9
references: 15516961
references: Nature. 2008 Mar 13;452(7184):230-3
references: 18337823
references: J Intern Med. 2010 May;267(5):515-25
references: 20433578
references: Cancer Res. 2004 Sep 1;64(17):6160-5
references: 15342400
references: Cancer Cell. 2013 Feb 11;23(2):143-58
references: 23352126
references: J Physiol. 2000 Dec 1;529 Pt 2:285-93
references: 11101640
references: J Cell Physiol. 2013 Sep;228(9):1854-62
references: 23459996
references: Cancer Res. 2012 Aug 15;72(16):3938-47
references: 22719070
references: Cancer Res. 1996 Mar 15;56(6):1194-8
references: 8640796
references: Biochem J. 1994 Nov 1;303 ( Pt 3):755-9
references: 7980443
references: Physiol Rev. 2012 Oct;92(4):1865-913
references: 23073633
references: Oncogene. 1994 Oct;9(10):2877-88
references: 8084592
references: Physiol Rev. 1981 Apr;61(2):296-434
references: 7012859
references: J Biol Chem. 2008 Jul 18;283(29):20473-83
references: 18482982
references: FASEB J. 2000 Nov;14(14):2185-97
references: 11053239
references: Int J Cancer. 2012 Apr 1;130(7):1511-20
references: 21484790
references: Radiother Oncol. 2011 Jun;99(3):424-31
references: 21676479
references: J Biol Chem. 2012 Jan 27;287(5):3392-402
references: 22170054
references: Cancer Res. 2009 Mar 15;69(6):2260-8
references: 19276390
references: Carcinogenesis. 2012 Dec;33(12):2432-40
references: 22962303
references: Cell. 1994 Mar 11;76(5):865-73
references: 8124722
references: Science. 2011 Nov 4;334(6056):678-83
references: 22053050
references: Autophagy. 2008 Oct;4(7):849-50
references: 18758232
references: Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L867-74
references: 15964895
references: Neuro Oncol. 2013 Feb;15(2):172-88
references: 23258846
references: Biochim Biophys Acta. 2012 Nov;1818(11):2687-706
references: 22705263
references: Adv Physiol Educ. 2004 Dec;28(1-4):160-79
references: 15545345
references: J Transl Med. 2010 Jun 15;8:57
references: 20550689
references: Novartis Found Symp. 2001;240:186-96; discussion 196-8
references: 11727929
references: Am J Physiol. 1993 Oct;265(4 Pt 1):C1015-29
references: 8238296
references: Adv Enzyme Regul. 2010;50(1):20-33
references: 19895836
references: Cancer Res. 2013 Aug 1;73(15):4616-28
references: 23752692
references: J Biol Chem. 2006 Apr 7;281(14):9030-7
references: 16452478
references: FEBS Lett. 1985 Oct 7;190(1):115-9
references: 4043390
references: Pflugers Arch. 2010 Nov;460(6):953-64
references: 20683624
references: Curr Opin Cell Biol. 2010 Apr;22(2):177-80
references: 20022734
references: Clin Cancer Res. 2004 Oct 1;10(19):6661-8
references: 15475456
references: Cancer Res. 2009 Jan 1;69(1):358-68
references: 19118021
references: Science. 2009 May 22;324(5930):1029-33
references: 19460998
references: J Clin Invest. 2008 Dec;118(12):3930-42
references: 19033663
references: Gut. 2009 Oct;58(10):1391-8
references: 19505879
references: Cancer Res. 2007 Jun 1;67(11):5408-17
references: 17545622
references: Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L941-9
references: 16766575
references: Exp Cell Res. 2010 Sep 10;316(15):2538-53
references: 20542029
references: J Cell Physiol. 2011 Feb;226(2):299-308
references: 20857482
references: Clin Cancer Res. 2012 Jun 1;18(11):3100-11
references: 22498007
references: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3071-6
references: 21282642
references: Cell. 1989 Jan 27;56(2):271-80
references: 2536298
references: FEBS Lett. 2004 Nov 19;577(3):439-45
references: 15556624
references: Nat Rev Drug Discov. 2008 Feb;7(2):168-81
references: 18167490
references: Proc Natl Acad Sci U S A. 1982 Jul;79(13):3935-9
references: 6287453
references: Cell. 2012 Feb 3;148(3):399-408
references: 22304911
references: Nat Rev Drug Discov. 2011 Sep 16;10(10):767-77
references: 21921921
references: Cancer Cell. 2013 Mar 18;23(3):302-15
references: 23477830
references: Biochem J. 2000 Aug 15;350 Pt 1:219-27
references: 10926847
references: Br J Cancer. 2007 Sep 3;97(5):646-53
references: 17687336
references: Cell Metab. 2006 Mar;3(3):187-97
references: 16517406
references: J Bioenerg Biomembr. 2012 Feb;44(1):127-39
references: 22407107
references: Science. 1932 Apr 1;75(1944):362-4
references: 17750037
references: J Biol Chem. 2006 Jul 14;281(28):19241-50
references: 16687407
references: Nature. 2010 Jun 17;465(7300):942-6
references: 20526321
references: J Cell Physiol. 2013 Apr;228(4):743-52
references: 22949268
references: J Biol Chem. 2008 Aug 1;283(31):21655-67
references: 18539591
references: Clin Cancer Res. 2003 Jun;9(6):2366-73
references: 12796407
references: Int J Cancer. 2010 Jul 1;127(1):207-19
references: 19876915
references: Radiother Oncol. 1984 Dec;2(4):343-66
references: 6097949
references: Pflugers Arch. 2008 Feb;455(5):799-810
references: 17943310
references: PLoS One. 2011;6(5):e20143
references: 21629657
references: EMBO J. 2000 Aug 1;19(15):3896-904
references: 10921872
references: Nat Chem Biol. 2005 Dec;1(7):371-6
references: 16370372
references: Int J Cancer. 2013 Mar 15;132(6):1288-99
references: 22907202
references: Ann Thorac Surg. 2008 Apr;85(4):1261-70
references: 18355507
references: Nat Genet. 2009 May;41(5):585-90
references: 19330027
references: Cancer Res. 2006 Jul 1;66(13):6699-707
references: 16818644
references: J Biol Chem. 2005 Dec 2;280(48):39882-9
references: 16174776
references: Proc Natl Acad Sci U S A. 1984 Aug;81(15):4833-7
references: 6087349
references: J Magn Reson Imaging. 2002 Oct;16(4):430-50
references: 12353258
references: IUBMB Life. 2012 Jan;64(1):1-9
references: 22131303
references: Nat Rev Cancer. 2008 Jan;8(1):56-61
references: 18059462
references: Nature. 1976 Aug 19;262(5570):661-4
references: 8729
references: Nat Rev Cancer. 2010 Apr;10(4):267-77
references: 20300106
references: Trends Mol Med. 2012 Sep;18(9):524-33
references: 22749019
references: Brain Res. 2010 Dec 2;1363:159-69
references: 20869350
references: Pflugers Arch. 2004 Feb;447(5):495-509
references: 14722772
references: J Urol. 2012 Aug;188(2):624-31
references: 22704445
references: Nature. 2013 May 30;497(7451):633-7
references: 23665962
references: Cancer Res. 2011 May 1;71(9):3364-76
references: 21415165
references: Nat Rev Mol Cell Biol. 2010 Jan;11(1):50-61
references: 19997129
references: Mol Pharmacol. 2007 Mar;71(3):942-8
references: 17178925
references: J Cell Biol. 2010 Feb 22;188(4):547-63
references: 20156964
references: Cancer Res. 1995 Jan 15;55(2):434-9
references: 7812975
references: Nat Rev Cancer. 2012 Jun 14;12(7):487-93
references: 22695393
references: Cell Metab. 2006 Mar;3(3):177-85
references: 16517405
references: Science. 1956 Aug 10;124(3215):269-70
references: 13351639
references: Blood. 2000 Feb 15;95(4):1427-34
references: 10666221
references: Curr Opin Pharmacol. 2008 Apr;8(2):133-40
references: 18222727
references: Cancer Res. 2009 Nov 15;69(22):8636-44
references: 19887620
references: PLoS One. 2011;6(6):e21549
references: 21738705
references: J Biol Chem. 2012 Aug 31;287(36):30664-76
references: 22761435
references: Oncogene. 2010 Dec 16;29(50):6509-21
references: 20890298
references: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2037-42
references: 20133848
references: Oncogene. 2013 Oct 31;32(44):5210-9
references: 23208505
references: Am J Physiol Cell Physiol. 2009 Mar;296(3):C414-21
references: 19073896
references: J Biol Chem. 1983 Mar 25;258(6):3503-8
references: 6300047
references: Front Oncol. 2013 Jan 07;2:199
references: 23316475
references: Cancer Res. 1986 Jun;46(6):2821-6
references: 3698008
references: Biochim Biophys Acta. 1991 Jun 18;1065(2):261-8
references: 1647821
references: Cell Struct Funct. 1998 Feb;23(1):33-42
references: 9639028
references: J Biol Chem. 2007 Jan 12;282(2):1409-21
references: 17090540
references: Cancer Res. 1989 Jan 1;49(1):205-11
references: 2535690
references: Am J Physiol. 1993 Apr;264(4 Pt 1):C761-82
references: 8476015
references: Br J Cancer. 1994 Oct;70(4):617-24
references: 7917906
references: Exp Cell Res. 1986 Jun;164(2):282-94
references: 3011468
references: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16663-8
references: 21930917
references: Biochim Biophys Acta. 2010 Feb;1804(2):410-21
references: 19879980
references: Cancer Res. 2007 May 1;67(9):4182-9
references: 17483329
references: Cancer Res. 2000 Dec 15;60(24):7075-83
references: 11156414
references: Nat Med. 1997 Feb;3(2):177-82
references: 9018236
references: J Biol Chem. 1984 May 10;259(9):5809-15
references: 6325450
references: Nature. 1982 Sep 9;299(5879):161-3
references: 7110335
references: J Cell Biol. 1989 Feb;108(2):377-87
references: 2918022
references: Cancer Cell. 2006 Jun;9(6):425-34
references: 16766262
references: Nature. 2006 May 25;441(7092):437-43
references: 16724055
references: PLoS One. 2012;7(4):e35949
references: 22563426