UCP2 - Taking the heat out of P-glycoprotein?

Abstract

Cancer cells are highly proliferative, invasive, metastatic and initiate angiogenesis. These activities demand plentiful energy and bountiful stores of anabolic precursors, a situation that puts significant strain on metabolic pathways and necessitates juggling of finite resources. However, the location and erratic structural organisation of tumours means they reside in a nutrient-poor environment. The glycolytic phenotype has evolved in cancer cells to provide a suitable balance between bioenergetic and biosynthetic pathways. Does this adopted strategy also support the overexpression of an ATP-dependent transporter (P-glycoprotein) to maintain resistance against chemotherapy? This article highlights the metabolic adaptations used by cancer cells to maintain both a glycolytic phenotype and sustain the activity of P-glycoprotein. We argue that these cells negotiate an energy precipice to achieve these adaptations. Finally, we advocate the use of compounds that place resistant cells expressing P-glycoprotein under further metabolic strain and how uncoupling protein-2 may provide an ideal target for them.

Keywords

P-glycoprotein / multidrug resistance / uncoupling protein / glycolytic phenotype / chemotherapy / mitochondria / collateral sensitivity

References

[1] Mellor HR.Resistance to chemotherapy in cancer: a complex and integrated cellular response..Pharmacology2008;81:275-300

[2] Dano K.Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells..Biochim Biophys Acta1973;323:466-83

[3] Ling V.Reduced permeability in CHO cells as a mechanism of resistance to colchicine,.J Cell Physiol1974;83:103-16

[4] Crowley E,Callaghan R.Generating inhibitors of P-glycoprotein: where to, now?.Methods Mol Biol2010;596:405-32 PMCID:PMC7121335

[5] Modok S,Callaghan R.Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer..Curr Opin Pharmacol2006;6:350-4

[6] Amiri-Kordestani L,Kurdziel K,Bates SE.Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies..Drug Resist Updat2012;15:50-61 PMCID:PMC3680361

[7] Shaffer BC,Patel C,Bates SE.Drug resistance: still a daunting challenge to the successful treatment of AML..Drug Resist Updat2012;15:62-9 PMCID:PMC3348380

[8] Feron O.Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells..Radiother Oncol2009;92:329-33

[9] Koppenol WH,Dang CV.Otto Warburg’s contributions to current concepts of cancer metabolism..Nat Rev Cancer2011;11:325-37

[10] Ward PS.Metabolic reprogramming: a cancer hallmark even warburg did not anticipate..Cancer Cell2012;21:297-308 PMCID:PMC3311998

[11] Vander Heiden MG,Thompson CB.Understanding the Warburg effect: the metabolic requirements of cell proliferation..Science2009;324:1029-33 PMCID:PMC2849637

[12] Hubackova S,Davidova E,Rohlena J.Mitochondria-driven elimination of cancer and senescent cells..Biol Chem2019;400:141-8

[13] Bloch K,van Hamel Parsons V.Metabolic alterations during the growth of tumour spheroids..Cell Biochem Biophys2014;68:615-28

[14] Mazurek S.Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells..Int J Biochem Cell Biol2011;43:969-80

[15] Schell JC,Jiang L.A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth..Mol Cell2014;56:400-13 PMCID:PMC4268416

[16] Vacanti NM,Green CR.Regulation of substrate utilization by the mitochondrial pyruvate carrier..Mol Cell2014;56:425-35 PMCID:PMC4267523

[17] Dimmer KS,Lang F,Bröer S.The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells..Biochem J2000;350:219-27 PMCID:PMC1221245

[18] Halestrap AP.The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation..Biochem J1999;343:281-99 PMCID:PMC1220552

[19] Pérez-Escuredo J,Sboarina M.Monocarboxylate transporters in the brain and in cancer..Biochim Biophys Acta2016;1863:2481-97 PMCID:PMC4990061

[20] Thews O,Kelleher DK,Gekle M.Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs..Neoplasia2006;143-52 PMCID:PMC1578510

[21] Liang BC.Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines..J Neurooncol1996;29:149-55

[22] Sanna K.Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro..Int J Cancer1994;58:258-62

[23] Icard P,Steyaert JM,Lincet H.The metabolic cooperation between cells in solid cancer tumors..Biochim Biophys Acta2014;1846:216-25

[24] Koukourakis MI,Mitrakas AG.Metabolic cooperation between co-cultured lung cancer cells and lung fibroblasts..Lab Invest2017;97:1321-31

[25] Rattigan YI,Ackerstaff E.Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment..Exp Cell Res2012;318:326-35 PMCID:PMC3402174

[26] Cadenas E.Mitochondrial free radical generation, oxidative stress, and aging..Free Radic Biol Med2000;29:222-30

[27] Mailloux RJ.Uncoupling proteins and the control of mitochondrial reactive oxygen species production..Free Radic Biol Med2011;51:1106-15

[28] Bell EL,Eisenbart J.The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production..J Cell Biol2007;177:1029-36 PMCID:PMC2064363

[29] Treberg JR,Brand MD.Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I)..J Biol Chem2011;286:27103-10 PMCID:PMC3149303

[30] Patterson JC,van de Kooij B,Lauffenburger DA.ROS and oxidative stress are elevated in mitosis during asynchronous cell cycle progression and are exacerbated by mitotic arrest..Cell Syst2019;8:163-7.e2 PMCID:PMC6688173

[31] Chetram MA,Hinton CV.ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells..Biochem Biophys Res Commun2011;410:195-200 PMCID:PMC3163383

[32] Leslie NR,Lindsay YE,Gray A.Redox regulation of PI 3-kinase signalling via inactivation of PTEN..EMBO J2003;225501-10 PMCID:PMC213768

[33] Chandel NS,Goldwasser E,Simon MC.Mitochondrial reactive oxygen species trigger hypoxia-induced transcription..Proc Natl Acad Sci U S A1998;95:11715-20 PMCID:PMC21706

[34] Echtay KS,Frischmuth K.Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone)..Proc Natl Acad Sci U S A2001;98:1416-21 PMCID:PMC29271

[35] Jaburek M.Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10..J Biol Chem2003;278:25825-31

[36] Vozza A,De Leonardis F.UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation..Proc Natl Acad Sci U S A2014;111:960-5 PMCID:PMC3903233

[37] Mailloux RJ,Bouillaud F,Collins S.Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3..J Biol Chem2011;286:21865-75 PMCID:PMC3122241

[38] Koziel A,Jarmuszkiewicz W.Increased activity of mitochondrial uncoupling protein 2 improves stress resistance in cultured endothelial cells exposed in vitro to high glucose levels..Am J Physiol Heart Circ Physiol2015;309:H147-56

[39] Sreedhar A.Uncoupling protein 2 and metabolic diseases..Mitochondrion2017;34:135-140 PMCID:PMC5477468

[40] Broxterman HJ,Kuiper CM,Lankelma J.Glycolysis in P-glycoprotein-overexpressing human tumor cell lines. Effects of resistance-modifying agents..FEBS Lett1989;247:405-10

[41] Carey Hulyer AR,O’Mara ML,Harmer JR.Cross-linking, DEER-spectroscopy and molecular dynamics confirm the inward facing state of P-glycoprotein in a lipid membrane..J Struct Biol2020;211:107513

[42] Dalla Pozza E,Dando I.Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine..Biochim Biophys Acta2012;1823:1856-63

[43] Donadelli M,Dalla Pozza E.Mitochondrial uncoupling protein 2 and pancreatic cancer: a new potential target therapy..World J Gastroenterol2015;21:3232-8 PMCID:PMC4363752

[44] Lopes-Rodrigues V,Mleczko J.Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles..Sci Rep2017;7:44541 PMCID:PMC5356019

[45] Echtay KS,St-Pierre J.Superoxide activates mitochondrial uncoupling proteins..Nature2002;415:96-9

[46] Pecqueur C,Ricquier D.UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism?.IUBMB Life2009;61:762-7

[47] Diano S.Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism..Trends Mol Med2012;18:52-8

[48] Al-Shawi MK,Omote H.Transition state analysis of the coupling of drug transport to ATP hydrolysis by P-glycoprotein..J Biol Chem2003;278:52629-40

[49] Garrigos M,Mir LM.Absence of cooperativity for MgATP and verapamil effects on the ATPase activity of P-glycoprotein containing membrane vesicles..Biochem Biophys Res Commun1993;196:1034-41

[50] Schroeder JS,Parker JD,Woods C.Antman EM.Chapter 7 - Pharmacologic Options for Treatment of Ischemic Disease..Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease (Fourth Edition).2013;W.B. Saunders, Philadelphia83-130

[51] Ferrari R.Calcium channel blockers and ischaemic heart disease: theoretical expectations and clinical experience..Eur Heart J.1991;12 Suppl F:18-24

[52] Vais H,Mak DD,Payne R,Foskett JK.EMRE is a matrix Ca(2+) sensor that governs gatekeeping of the mitochondrial Ca(2+) uniporter..Cell Rep2016;14:403-10 PMCID:PMC4731249

[53] Koo WS,Burke TJ.Verapamil attenuates calcium-induced mitochondrial swelling and respiratory dysfunction..J Pharmacol Exp Ther1995;273:206-12

[54] Ponne S,Boopathy R.Verapamil attenuates scopolamine induced cognitive deficits by averting oxidative stress and mitochondrial injury - A potential therapeutic agent for Alzheimer’s Disease..Metab Brain Dis2020;35:503-15

[55] Harper ME,Villalobos-Menuey E.Characterization of a novel metabolic strategy used by drug-resistant tumor cells..FASEB J2002;16:1550-7