Advertisement

Inflammopharmacology

, Volume 23, Issue 6, pp 365–369 | Cite as

Overexpression of uncoupling protein-2 in cancer: metabolic and heat changes, inhibition and effects on drug resistance

  • Michael A. Pitt
Commentary

Abstract

This paper deals with the role of uncoupling protein-2 (UCP2) in cancer. UCP2 is overexpressed in cancer. This overexpression results in uncoupling of mitochondrial oxidative phosphorylation and a shift in production of ATP from mitochondrial oxidative phosphorylation to cytosolic aerobic glycolysis. UCP2 overexpression results in the following changes. Mitochondrial membrane potential (Δψ m) is decreased and lactate accumulates. There is a diminished production of reactive oxygen species and apoptosis is inhibited post-exposure to chemotherapeutic agents. There is an increase in heat and entropy production and a departure from the stationary state of non-cancerous tissue. Uncoupling of oxidative phosphorylation may also be caused by protonophores and non-steroidal anti-inflammatory drugs. UCP2 requires activation by superoxide and lipid peroxidation derivatives. As vitamin E inhibits lipid peroxidation, it might be expected that vitamin E would act as a chemotherapeutic agent against cancer. A recent study has shown that vitamin E and another anti-oxidant accelerate cancer progression. UCP2 is inhibited by genipin, chromane compounds and short interfering RNAs (siRNA). Genipin, chromanes and siRNA are taken up by both cancer and non-cancerous cells. Targeting the uptake of these agents by cancer cells by the enhanced permeability and retention effect is considered. Inhibition of UCP2 enhances the action of several anti-cancer agents.

Keywords

Cancer Uncoupling protein-2 overexpression Uncoupling protein-2 inhibition Non-steroidal anti-inflammatory drugs Vitamin E Uncoupling protein-2 inhibition effect on chemotherapeutic agents 

Notes

Compliance with ethical standards

Conflict of interest

The author, Dr Michael A Pitt, states that there is no actual, potential or perceived conflict of interest in regard to this paper.

References

  1. Baffy G, Derdak Z, Robson SC (2011) Mitochondrial recoupling: a novel therapeutic strategy for cancer? Br J Cancer 105:469–474PubMedCentralCrossRefPubMedGoogle Scholar
  2. Bieri JG, Anderson AA (1960) Peroxidation of lipids in tissue homogenates as related to vitamin E. Arch Biochem Biophys 90:105–110CrossRefGoogle Scholar
  3. Brand MD, Affourtit C, Estevez TC, Green K, Lambert AJ, Miwa S, Pakay JL, Parker N (2004) Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37:755–767CrossRefPubMedGoogle Scholar
  4. Carretero MV, Torres L, Latasa U, Garcia-Trevijano ER, Prieto J, Mato JM, Avila MA (1998) Transformed but not normal hepatocytes express UCP2. FEBS Lett 439:55–58CrossRefPubMedGoogle Scholar
  5. Dando I, Fiorini C, Pozza ED, Padroni C, Costanzo C, Palmieri M, Donadelli M (2013) UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells. Biochim Biophys Acta 1833:672–679CrossRefPubMedGoogle Scholar
  6. Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR, Baffy G (2008) The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 68:2813–2819PubMedCentralCrossRefPubMedGoogle Scholar
  7. Downey JE, Irving DH, Tappel AL (1978) Effects of dietary antioxidants on in vivo lipid peroxidation in the rat as measured by pentane production. Lipids 13:403–407CrossRefPubMedGoogle Scholar
  8. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99CrossRefPubMedGoogle Scholar
  9. Estevez P, Pecqueur C, Alves-Guerra MC (2015) UCP2 induces metabolic reprogramming to inhibit proliferation of cancer cells. Mol Cell Oncol 2(1):e975024CrossRefGoogle Scholar
  10. Harper ME, Antoniou A, Villelabos-Menuey E, Russo A et al (2002) Charactization of a novel metabolic strategy used by drug-resistant tumor cells. FASEB J 16:1550–1557CrossRefPubMedGoogle Scholar
  11. Horimoto M, Resnick MB, Konkin TA, Routhier J, Wands JR, Baffy G (2004) Expression of uncoupling protein-2 in human colon cancer. Clin Cancer Res 10:6203–6207CrossRefPubMedGoogle Scholar
  12. Hu ML, Frankel EN, Leibovitz BE, Tappel AL (1989) Effect of dietary lipids and vitamin E on in vitro lipid peroxidation in rat liver and kidney homogenates. J Nutr 119:1574–1582PubMedGoogle Scholar
  13. Jones C, Collins P, Choudhury S, Hodgson H, Damelin L (2005) Increased expression of uncoupling protein 2 in HepG2 cells attenuates oxidative damage and apoptosis. Liver Int 25:880–887CrossRefPubMedGoogle Scholar
  14. Julienne CM, Duma J-F, Goupille C, Pinault M, Berri C, Collin A, Tesseraud S, Couet C, Servais S (2012) Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency. J Cachexia Sarcopenia Muscle 3:265–275PubMedCentralCrossRefPubMedGoogle Scholar
  15. Kondepudi D, Prigogine I (1998) Modern thermodynamics: from heat engines to dissipative structures. Wiley, ChichesterGoogle Scholar
  16. Lawson RN, Chughtai MS (1963) Breast cancer and body temperature. Can Med Assoc J 88:68–70PubMedCentralPubMedGoogle Scholar
  17. Lawson RN, Gaston JP (1964) Temperature measurements of localised pathological processes. Ann N Y Acad Sci 121:90–98CrossRefPubMedGoogle Scholar
  18. Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41:189–207CrossRefPubMedGoogle Scholar
  19. Mailloux RJ, Adjeitey CN-K, Harper ME (2010) Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents. PLoS One. doi: 10.1371/Journal.PONE0013289 PubMedCentralPubMedGoogle Scholar
  20. McCay PB, Poyer JL, Pfeifer PM, May HE, Gilliam JM (1971) A function for α-tocopherol: Stabilization of the microsomal membrane from radical attack during TPNH-dependent oxidations. Lipids 6:297–306CrossRefGoogle Scholar
  21. Mingatto FE, Santos AC, Uyemura SA, Jordani MC, Curti C (1996) In vitro interaction of nonsteroidal anti-inflammatory drugs on oxidative phosphorylation of rat kidney mitochondria: respiration and ATP synthesis. Arch Biochem Biophys 334:303–308CrossRefPubMedGoogle Scholar
  22. Moreno-Sánchez R, Vásquez C, Ayala G, Silveira LH, Martínez-Lavin M (1999) Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs: study in mitochondria, submitochondrial particles, cells, and whole heart. Biochem Pharmacol 57:743–752CrossRefPubMedGoogle Scholar
  23. Petrescu I, Tarba C (1997) Uncoupling effects of diclofenac and aspirin in the perfused liver and isolated hepatic mitochondria of rat. Biochim Biophys Acta 1318:385–394CrossRefPubMedGoogle Scholar
  24. Pitt MA (2015) Increased temperature and entropy production in cancer: the role of anti-inflammatory drugs. Inflammopharmacology 23:17–20CrossRefPubMedGoogle Scholar
  25. Pitt MA, Jones PD (1975) Effect of aqueous acetone extractions and vitamin E on NADPH-dependent lipid peroxidation of sheep and rat liver microsomes. Int J Biochem 6:505–511CrossRefGoogle Scholar
  26. Pons DG, Nadal-Serrano M, Torrens-Mas M, Valle A, Oliver J, Roca P (2015) UCP2 inhibition sensitizes breast cancer cells to therapeutic agents by increasing oxidative stress. Free Radic Biol Med 86:67–77CrossRefPubMedGoogle Scholar
  27. Pozza ED, Fiorini C, Dando I, Menegazzi M, Sgarbossa A, Costanzo C, Palmieri M, Donadelli M (2012) Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine. Biochim Biophys Acta 1823:1856–1863CrossRefPubMedGoogle Scholar
  28. Rial E, Rodríguez-Sánchez L, Aller P, Guisado A, González-Barroso MM, Gallardo-Vara E, Redondo-Horchajo M, Castellanos E, Ferández de la Pradillo R, Viso A (2011) Development of chromanes as novel inhibitors of the uncoupling proteins. Chem Biol 18:264–274CrossRefPubMedGoogle Scholar
  29. Samudio I, Fiegl M, McQueen T, Clise-Dwyer K, Andreeff M (2008) The Warburg effect in leukaemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res 68:5198–5205PubMedCentralCrossRefPubMedGoogle Scholar
  30. Samudio I, Fiegl M, Andreeff M (2009) Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism. Cancer Res 69:2163–2166CrossRefPubMedGoogle Scholar
  31. Sanchis D, Busquets S, Alvarez B, Ricquier D, López-Soriano FJ, Argilés JM (1998) Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model. FEBS Lett 436:415–418CrossRefPubMedGoogle Scholar
  32. Santandreu FM, Roca P, Oliver J (2010) Uncoupling protein-2 knockdown mediates the cytotoxic effects of cisplatin. Free Radic Biol Med 49:658–666CrossRefPubMedGoogle Scholar
  33. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO (2014) Antioxidants accelerate lung cancer progression in mice. Sci Trans Med 6:221ra15CrossRefGoogle Scholar
  34. Stefanadis C, Chrysochoou C, Markou D, Petraki K, Panagiotakos DB, Fasoulakis C, Kyriakidis A, Papadimitriou C, Toutouzas PK (2001) Increased temperature of malignant urinary bladder tumors in vivo: the application of a new method based on a catheter technique. J Clin Oncol 19:676–681PubMedGoogle Scholar
  35. Stefanadis C, Chrysohoou C, Panagiotakos DB, Passalidou E, Katsi V, Polychronopoulos V, Toutouzas PK (2003) Temperature differences are associated with malignancy on lung lesions: a clinical study. BMC Cancer 3:1. doi: 10.1186/1471-2407-3-1 PubMedCentralCrossRefPubMedGoogle Scholar
  36. Ulrich CM, Bigler J, Potter JD (2006) Non-steroidal anti-inflammatory drugs for cancer prevention: promises, perils and pharmacogenetics. Nat Rev Cancer 6:130–140CrossRefPubMedGoogle Scholar
  37. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033PubMedCentralCrossRefPubMedGoogle Scholar
  38. Warburg O (1956) On the origin of cancer cells. Science 123:309–314CrossRefPubMedGoogle Scholar
  39. Zhang CY, Parton LE, Ye CP, Krauss S, Shen R, Lin CT, Porco JA, Lowell BB (2006) Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab 3:417–427CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  1. 1.ParaparaumuNew Zealand

Personalised recommendations