Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Journal of Clinical Investigation

Volumn 118, Issue 12, 2008, Pages 3930-3942

  Sonveaux, Pierre ^a,b   Végran, Frédérique ^a   Schroeder, Thies ^b   Wergin, Melanie C ^b   Verrax, Julien ^a   Rabbani, Zahid N ^b   De Saedeleer, Christophe J ^a   Kennedy, Kelly M ^b   Diepart, Caroline ^a   Jordan, Bénédicte F ^a   Kelley, Michael J ^b   Gallez, Bernard ^a   Wahl, Miriam L ^b   Feron, Olivier ^a   Dewhirst, Mark W ^b  

^a UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

^b DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA CYANO 4 HYDROXYCINNAMIC ACID; LACTIC ACID; MONOCARBOXYLATE TRANSPORTER 1; SMALL INTERFERING RNA;

AEROBIC METABOLISM; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER INHIBITION; CELL RESPIRATION; COLORECTAL CARCINOMA; CONTROLLED STUDY; GLYCOLYSIS; HUMAN; HUMAN CELL; HYPOXIA; LUNG CARCINOMA; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SQUAMOUS CELL CARCINOMA; TUMOR CELL; UTERINE CERVIX CARCINOMA;

ANIMALS; CELL HYPOXIA; CELL LINE, TUMOR; DRUG DELIVERY SYSTEMS; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUCOSE; GLYCOLYSIS; HUMANS; LACTIC ACID; MICE; MICE, INBRED BALB C; MONOCARBOXYLIC ACID TRANSPORTERS; NEOPLASM TRANSPLANTATION; NEOPLASMS, EXPERIMENTAL; OXIDATION-REDUCTION; OXYGEN; SYMPORTERS; TRANSPLANTATION, HETEROLOGOUS;

EID: 57449097020     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI36843     Document Type: Article

References (51)

1. Wu, R., and Racker, E. 1959. Regulatory mechanisms in carbohydrate metabolism. IV. Pasteur effect and Crabtree effect in ascites tumor cells. J. Biol. Chem. 234:1036-1041.
2. Dewhirst, M.W. 1998. Concepts of oxygen transport at the microcirculatory level. Semin. Radiat. Oncol. 8:143-150.
3. Dewhirst, M.W. 2003. Mechanisms underlying hypoxia development in tumors. Adv. Exp. Med. Biol. 510:51-56.
4. Dang, C.V., and Semenza, G.L. 1999. Oncogenic alterations of metabolism. Trends Biochem. Sci. 24:68-72.
5. Warburg, O. 1930. The metabolism of tumors. Constable. London, United Kingdom. 327 pp.
6. Semenza, G.L., et al. 2001. 'The metabolism of tumours':70 years later. Novartis Found. Symp. 240:251-260.
7. Vaupel, P.W. 1994. Blood flow, oxygenation, tissue pH distribution, and bioenergetic status of tumors. Lecture 23. Ernst Schering Research Foundation. Berlin, Germany. 79 pp.
8. Vaupel, P. 1996. Is there a critical tissue oxygen tension for bioenergetic status and cellular pH regulation in solid tumors? Experientia. 52:464-468.
9. Walenta, S., et al. 2001. Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model. Int. J. Radiat. Oncol. Biol. Phys. 51:840-848.
10. Kim, J.W., and Dang, C.V. 2006. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 66:8927-8930.
11. James, P.E., Jackson, S.K., Grinberg, O.Y., and Swartz, H.M. 1995. The effects of endotoxin on oxygen consumption of various cell types in vitro: an EPR oximetry study. Free Radic. Biol. Med. 18:641-647.
12. Halestrap, A.P., and Meredith, D. 2004. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 447:619-628.
13. Halestrap, A.P., and Price, N.T. 1999. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem. J. 343:281-299.
14. Baker, S.K., McCullagh, K.J., and Bonen, A. 1998. Training intensity-dependent and tissue-specific increases in lactate uptake and MCT-1 in heart and muscle. J. Appl. Physiol. 84:987-994.
15. Bonen, A., et al. 1998. Short-term training increases human muscle MCT1 and femoral venous lactate in relation to muscle lactate. Am. J. Physiol. 274:E102-E107.
16. Dubouchaud, H., Butterfield, G.E., Wolfel, E.E., Bergman, B.C., and Brooks, G.A. 2000. Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 278:E571-E579.
17. Manning Fox, J.E., Meredith, D., and Halestrap, A.P. 2000. Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J. Physiol. 529:285-293.
18. Spencer, T.L., and Lehninger, A.L. 1976. L-lactate transport in Ehrlich ascites-tumour cells. Biochem. J. 154:405-414.
19. Cheeti, S., Warrier, B.K., and Lee, C.H. 2006. The role of monocarboxylate transporters in uptake of lactic acid in HeLa cells. Int. J. Pharm. 325:48-54.
20. Hashimoto, T., Hussien, R., and Brooks, G.A. 2006. Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am. J. Physiol. Endocrinol. Metab. 290:E1237-E1244.
21. Jijakli, H., et al. 1996. Insulinotropic action of methyl pyruvate: enzymic and metabolic aspects. Arch. Biochem. Biophys. 335:245-257.
22. Koukourakis, M.I., Giatromanolaki, A., Harris, A.L., and Sivridis, E. 2006. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res. 66:632-637.
23. Asada, K., et al. 2003. Reduced expression of GNA11 and silencing of MCT1 in human breast cancers. Oncology. 64:380-388.
24. Stubbs, M., McSheehy, P.M., Griffiths, J.R., and Bashford, C.L. 2000. Causes and consequences of tumour acidity and implications for treatment. Mol. Med. Today. 6:15-19.
25. Brizel, D.M., et al. 2001. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 51:349-353.
26. Walenta, S., et al. 1997. Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am. J. Pathol. 150:409-415.
27. Walenta, S., et al. 2000. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 60:916-921.
28. Tanaka, M., et al. 2004. Role of lactate in the brain energy metabolism: revealed by Bioradiography. Neurosci. Res. 48:13-20.
29. Lee, Y.J., Kang, I.J., Bunger, R., and Kang, Y.H. 2003. Mechanisms of pyruvate inhibition of oxidantinduced apoptosis in human endothelial cells. Microvasc. Res. 66:91-101.
30. Pelicano, H., et al. 2006. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 175:913-923.
31. Dimmer, K.S., Friedrich, B., Lang, F., Deitmer, J.W., and Broer, S. 2000. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J. 350:219-227.
32. Ullah, M.S., Davies, A.J., and Halestrap, A.P. 2006. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J. Biol. Chem. 281:9030-9037.
33. Wahl, M.L., et al. 2002. Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol. Cancer Ther. 1:617-628.
34. Brown, J.M., and Wilson, W.R. 2004. Exploiting tumour hypoxia in cancer treatment. Nat. Rev. Cancer. 4:437-447.
35. Crabtree, H.G. 1929. Observations on the carbohydrate metabolism of tumours. Biochem. J. 23:536-545.
36. Pike, S.E., Markey, S.P., Ijames, C., Jones, K.D., and Tosato, G. 1991. The role of lactic acid in autocrine B-cell growth stimulation. Proc. Natl. Acad. Sci. U. S. A. 88:11081-11085.
37. Wang, Q., Lu, Y., and Morris, M.E. 2007. Monocarboxylate transporter (MCT) mediates the transport of gamma-hydroxybutyrate in human kidney HK-2 cells. Pharm. Res. 24:1067-1078.
38. Belt, J.A., Thomas, J.A., Buchsbaum, R.N., and Racker, E. 1979. Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavonoids. Biochemistry. 18:3506-3511.
39. Coss, R.A., Storck, C.W., Daskalakis, C., Berd, D., and Wahl, M.L. 2003. Intracellular acidification abrogates the heat shock response and compromises survival of human melanoma cells. Mol. Cancer Ther. 2:383-388.
40. Fang, J., et al. 2006. The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol. Pharmacol. 70:2108-2115.
41. Mathupala, S.P., Parajuli, P., and Sloan, A.E. 2004. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery. 55:1410-1419.
42. Froberg, M.K., et al. 2001. Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues. Neuroreport. 12:761-765.
43. Pinheiro, C., et al. 2008. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 452:139-146.
44. Taper, H.S., Woolley, G.W., Teller, M.N., and Lardis, M.P. 1966. A new transplantable mouse liver tumor of spontaneous origin. Cancer Res. 26:143-148.
45. King, M.P., and Attardi, G. 1989. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 246:500-503.
46. Sonveaux, P., et al. 2003. Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway: implications for tumor radiotherapy. Cancer Res. 63:1012-1019.
47. Del Prete, E., Lutz, T.A., and Scharrer, E. 2004. Inhibition of glucose oxidation by alpha-cyano-4-hydroxycinnamic acid stimulates feeding in rats. Physiol. Behav. 80:489-498.
48. Martinive, P., et al. 2006. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications for anticancer therapies. Cancer Res. 66:11736-11744.
49. Sonveaux, P., et al. 2002. Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery. FASEB J. 16:1979-1981.
50. Bouzin, C., Brouet, A., De Vriese, J., DeWever, J., and Feron, O. 2007. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J. Immunol. 178:1505-1511.
51. Feron, O., et al. 1996. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J. Biol. Chem. 271:22810-22814.