Disrupting proton dynamics and energy metabolism for cancer therapy

Key Points

  • In rapidly growing cancer cells, oncogenes and hypoxia stimulate glycolytic metabolism, which generates increased amounts of lactic and carbonic acids.

  • Several pH-regulating systems — Na+/H+ exchangers (NHEs), carbonic anhydrases (CAIX and CAXII), HCO3 transporters, lactate/H+ symporters (monocarboxylate transporter 1 (MCT1) and MCT4) and intracellular H+ pumps — are essential to maintain a permissive intracellular pH (pHi) to optimize bioenergetic metabolism, cell cycle progression, growth and survival.

  • Cells lacking pH-regulating capabilities can enter growth arrest or can be 'killed' by H+. Targeting pH-regulating proteins in isolation (NHE1, CAs, MCTs and H+ pumps) impairs tumour progression.

  • Targeting the export of lactic acid from tumour cells (by disrupting MCTs) reduces glycolysis and growth rates, thus sensitizing tumour cells to treatment with mitochondrial complex I inhibitors (such as metformin and phenformin).

  • We propose the development of an acute 'metabolic knife' treatment that combines targeting of pH control and ATP-driven metabolism to eradicate rapidly growing glycolytic tumours.

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'.

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Figure 1: The tumour microenvironment presents unique conditions that drive tumour development.
Figure 2
Figure 3: Targeting cellular acidification for tumour cell death: proof of concept.
Figure 4: Membrane transport metabolons: HCO3 and lactate transport.
Figure 5: Physical limitations for the effective reduction of intracellular pH that would be permissive for cell killing.
Figure 6: Potential strategies to target metabolic-pH cellular interactions to induce 'metabolic catastrophe' and achieve tumour cell killing.

References

  1. 1

    Warburg, O. On respiratory impairment in cancer cells. Science 124, 269–270 (1956). In this article Warburg summarizes his work and describes the Warburg effect.

    CAS  PubMed  Google Scholar 

  2. 2

    Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Schulze, A. & Harris, A. L. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491, 364–373 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Pouyssegur, J., Dayan, F. & Mazure, N. M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    CAS  Google Scholar 

  7. 7

    Helmlinger, G., Yuan, F., Dellian, M. & Jain, R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ludwig, M. G. et al. Proton-sensing G-protein-coupled receptors. Nature 425, 93–98 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Tresguerres, M., Buck, J. & Levin, L. R. Physiological carbon dioxide, bicarbonate, and pH sensing. Pflugers Arch. 460, 953–964 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Casey, J. R., Grinstein, S. & Orlowski, J. Sensors and regulators of intracellular pH. Nature Rev. Mol. Cell Biol. 11, 50–61 (2010).

    CAS  Google Scholar 

  11. 11

    Semenza, G. L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012). A current review of HIF treatment by a leading expert in the field.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Gillies, R. J., Verduzco, D. & Gatenby, R. A. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nature Rev. Cancer 12, 487–493 (2012). This Review summarizes recent opinion on evolutionary game theory of carcinogenesis with a particular emphasis on hypoxia and acidosis.

    CAS  Google Scholar 

  13. 13

    Chiche, J., Ilc, K., Brahimi-Horn, M. C. & Pouyssegur, J. Membrane-bound carbonic anhydrases are key pH regulators controlling tumor growth and cell migration. Adv. Enzyme Regul. 50, 20–33 (2010).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B. & Gillies, R. J. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).

    CAS  PubMed  Google Scholar 

  15. 15

    Neri, D. & Supuran, C. T. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Rev. Drug Discov. 10, 767–777 (2011). A major recent review of pH-targeted clinical therapy developments.

    CAS  Google Scholar 

  16. 16

    Parks, S. K., Chiche, J. & Pouyssegur, J. pH control mechanisms of tumor survival and growth. J. Cell. Physiol. 226, 299–308 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Swietach, P., Hulikova, A., Vaughan-Jones, R. D. & Harris, A. L. New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene 29, 6509–6521 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Chiche, J. et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 69, 358–368 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Parks, S. K., Mazure, N. M., Counillon, L. & Pouyssegur, J. Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels. J. Cell. Physiol. 228, 1854–1862 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Swietach, P., Patiar, S., Supuran, C. T., Harris, A. L. & Vaughan-Jones, R. D. The role of carbonic anhydrase 9 in regulating extracellular and intracellular pH in three-dimensional tumor cell growths. J. Biol. Chem. 284, 20299–20310 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Swietach, P. et al. Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths. J. Biol. Chem. 283, 20473–20483 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Cardone, R. A., Casavola, V. & Reshkin, S. J. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Rev. Cancer 5, 786–795 (2005).

    CAS  Google Scholar 

  23. 23

    Reshkin, S. J. et al. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J. 14, 2185–2197 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Chiche, J. et al. In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. Int. J. Cancer 130, 1511–1520 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Le Floch, R. et al. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc. Natl Acad. Sci. USA 108, 16663–16668 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Ullah, M. S., Davies, A. J. & Halestrap, A. P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J. Biol. Chem. 281, 9030–9037 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Huber, V. et al. Proton dynamics in cancer. J. Transl. Med. 8, 57 (2010).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Johnson, J. D. & Epel, D. Intracellular pH and activation of sea urchin eggs after fertilisation. Nature 262, 661–664 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Aronson, P. S., Nee, J. & Suhm, M. A. Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles. Nature 299, 161–163 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Kopito, R. R. & Lodish, H. F. Primary structure and transmembrane orientation of the murine anion exchange protein. Nature 316, 234–238 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Sardet, C., Franchi, A. & Pouyssegur, J. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell 56, 271–280 (1989). The first full molecular structure of a Na+/H+ exchanger, NHE1.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Pouyssegur, J., Sardet, C., Franchi, A., L'Allemain, G. & Paris, S. A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc. Natl Acad. Sci. USA 81, 4833–4837 (1984). This paper describes the development of the H+ suicide technique through manipulation of Na+ and H+ transport.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Chambard, J. C. & Pouyssegur, J. Intracellular pH controls growth factor-induced ribosomal protein S6 phosphorylation and protein synthesis in the G0→G1 transition of fibroblasts. Exp. Cell Res. 164, 282–294 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Pouyssegur, J., Franchi, A., L'Allemain, G. & Paris, S. Cytoplasmic pH, a key determinant of growth factor-induced DNA synthesis in quiescent fibroblasts. FEBS Lett. 190, 115–119 (1985). A demonstration that pH i is a determinant for controlling cell cycle entry.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Pouyssegur, J., Franchi, A. & Pages, G. pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. Novartis Found. Symp. 240, 186–198 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    L'Allemain, G., Paris, S. & Pouyssegur, J. Growth factor action and intracellular pH regulation in fibroblasts. Evidence for a major role of the Na+/H+ antiport. J. Biol. Chem. 259, 5809–5815 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Pouyssegur, J., Chambard, J. C., Franchi, A., Paris, S. & Van Obberghen-Schilling, E. Growth factor activation of an amiloride-sensitive Na+/H+ exchange system in quiescent fibroblasts: coupling to ribosomal protein S6 phosphorylation. Proc. Natl Acad. Sci. USA 79, 3935–3939 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Balgi, A. D. et al. Regulation of mTORC1 signaling by pH. PLoS ONE 6, e21549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Luo, J. & Tannock, I. F. Inhibition of the regulation of intracellular pH: potential of 5-(N,N-hexamethylene) amiloride in tumour-selective therapy. Br. J. Cancer 70, 617–624 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Rich, I. N., Worthington-White, D., Garden, O. A. & Musk, P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na+/H+ exchanger. Blood 95, 1427–1434 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Kumar, A. P. et al. Repression of NHE1 expression by PPARγ activation is a potential new approach for specific inhibition of the growth of tumor cells in vitro and in vivo. Cancer Res. 69, 8636–8644 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Beltran, A. R. et al. NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells. Pflugers Arch. 455, 799–810 (2008). This study describes the expression of other NHE isoforms in a cancer cell line.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Wakabayashi, S., Shigekawa, M. & Pouyssegur, J. Molecular physiology of vertebrate Na+/H+ exchangers. Physiol. Rev. 77, 51–74 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Mentzer, R. M. Jr et al. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann. Thorac Surg. 85, 1261–1270 (2008).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Avkiran, M., Cook, A. R. & Cuello, F. Targeting Na+/H+ exchanger regulation for cardiac protection: a RSKy approach? Curr. Opin. Pharmacol. 8, 133–140 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Harley, W. et al. Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas. Brain Res. 1363, 159–169 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Reshkin, S. J. et al. Paclitaxel induces apoptosis via protein kinase A− and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clin. Cancer Res. 9, 2366–2373 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Rios, E. J., Fallon, M., Wang, J. & Shimoda, L. A. Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L867–874 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Shimoda, L. A., Fallon, M., Pisarcik, S., Wang, J. & Semenza, G. L. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L941–949 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Gatenby, R. A. et al. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br. J. Cancer 97, 646–653 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Lucien, F., Brochu-Gaudreau, K., Arsenault, D., Harper, K. & Dubois, C. M. Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PLoS ONE 6, e28851 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Hulikova, A., Harris, A. L., Vaughan-Jones, R. D. & Swietach, P. Regulation of intracellular pH in cancer cell lines under normoxia and hypoxia. J. Cell. Physiol. 228, 743–752 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Paris, S. & Pouyssegur, J. Biochemical characterization of the amiloride-sensitive Na+/H+ antiport in Chinese hamster lung fibroblasts. J. Biol. Chem. 258, 3503–3508 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Cosson, P., Curtis, I. D., Pouyssegur, J., Griffiths, G. & Davoust, J. Low cytoplasmic pH inhibitis endocytosis and transport from the trans-golgi network to the cell surface. J. Cell Biol. 108, 377–387 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Koivusalo, M. et al. Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J. Cell Biol. 188, 547–563 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Schwab, A., Fabian, A., Hanley, P. J. & Stock, C. Role of ion channels and transporters in cell migration. Physiol. Rev. 92, 1865–1913 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Supuran, C. T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Rev. Drug Discov. 7, 168–181 (2008).

    CAS  Google Scholar 

  59. 59

    Pastorek, J. et al. Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9, 2877–2888 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Wykoff, C. C. et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 60, 7075–7083 (2000). The first description of CAIX induction by HIF1.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Svastova, E. et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 577, 439–445 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Morris, J. C. et al. Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors. J. Med. Chem. 54, 6905–6918 (2011).

    CAS  PubMed  Google Scholar 

  63. 63

    Robertson, N., Potter, C. & Harris, A. L. Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res. 64, 6160–6165 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Lou, Y. et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 71, 3364–3376 (2011). This study shows that CAIX knockdown causes tumour regression and CAIX inhibitors stall tumour progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Lock, F. E. et al. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene http://dx.doi.org/10.1038/onc.2012.550 (2012).

  66. 66

    Doyen, J., Parks, S. K., Marcie, S., Pouyssegur, J. & Chiche, J. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis. Front. Oncol. 2, 199 (2013).

    PubMed  PubMed Central  Google Scholar 

  67. 67

    Dubois, L. et al. Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother. Oncol. 99, 424–431 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    McIntyre, A. et al. Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Clin. Cancer Res. 18, 3100–3111 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Proescholdt, M. A. et al. Function of carbonic anhydrase IX in glioblastoma multiforme. Neuro Oncol. 14, 1357–1366 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Parkkila, S. et al. The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian alpha-carbonic anhydrase isoforms. Bioorg. Med. Chem. Lett. 19, 4102–4106 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Siebels, M. et al. A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX®) and interferon-alpha-2a in metastatic renal cell carcinoma patients. World J. Urol. 29, 121–126 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Sterling, D., Reithmeier, R. A. & Casey, J. R. A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. J. Biol. Chem. 276, 47886–47894 (2001). The original publication proposing the membrane transport metabolon.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Boron, W. F. Evaluating the role of carbonic anhydrases in the transport of HCO3–-related species. Biochim. Biophys. Acta 1804, 410–421 (2010). The main critique of the membrane transport metabolon.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Lu, J. et al. Effect of human carbonic anhydrase II on the activity of the human electrogenic Na/HCO3 cotransporter NBCe1-A in Xenopus oocytes. J. Biol. Chem. 281, 19241–19250 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Piermarini, P. M., Kim, E. Y. & Boron, W. F. Evidence against a direct interaction between intracellular carbonic anhydrase II and pure C-terminal domains of SLC4 bicarbonate transporters. J. Biol. Chem. 282, 1409–1421 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Moraes, T. F. & Reithmeier, R. A. Membrane transport metabolons. Biochim. Biophys. Acta 1818, 2687–2706 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Becker, H. M. & Deitmer, J. W. Nonenzymatic proton handling by carbonic anhydrase II during H+-lactate cotransport via monocarboxylate transporter 1. J. Biol. Chem. 283, 21655–21667 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Becker, H. M., Klier, M., Schuler, C., McKenna, R. & Deitmer, J. W. Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II. Proc. Natl Acad. Sci. USA 108, 3071–3076 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Mount, D. B. & Romero, M. F. The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch. 447, 710–721 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Romero, M. F., Fulton, C. M. & Boron, W. F. The SLC4 family of HCO3– transporters. Pflugers Arch. 447, 495–509 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Wieth, J. O., Andersen, O. S., Brahm, J., Bjerrum, P. J. & Borders, C. L. Jr. Chloride–bicarbonate exchange in red blood cells: physiology of transport and chemical modification of binding sites. Phil. Trans. R. Soc. Lond. B 299, 383–399 (1982).

    CAS  Google Scholar 

  82. 82

    Ahmed, S. et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nature Genet. 41, 585–590 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Lauritzen, G. et al. NBCn1 and NHE1 expression and activity in ΔNErbB2 receptor-expressing MCF-7 breast cancer cells: contributions to pHi regulation and chemotherapy resistance. Exp. Cell Res. 316, 2538–2553 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Lauritzen, G. et al. The Na+/H+ exchanger NHE1, but not the Na+, HCO3– cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2. Cancer Lett. 317, 172–183 (2011).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Boedtkjer, E. et al. Contribution of Na+,HCO3–-cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int. J. Cancer 132, 1288–1299 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Lunt, S. Y. & Vander Heiden, M. G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    CAS  PubMed  Google Scholar 

  88. 88

    Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930–3942 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Brahimi-Horn, M. C., Bellot, G. & Pouyssegur, J. Hypoxia and energetic tumour metabolism. Curr. Opin. Genet. Dev. 21, 67–72 (2010).

    PubMed  PubMed Central  Google Scholar 

  92. 92

    Poole, R. C. & Halestrap, A. P. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am. J. Physiol. 264, C761–C782 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Halestrap, A. P. The monocarboxylate transporter family--Structure and functional characterization. IUBMB Life 64, 1–9 (2012).

    CAS  PubMed  Google Scholar 

  94. 94

    Garcia, C. K., Goldstein, J. L., Pathak, R. K., Anderson, R. G. & Brown, M. S. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 76, 865–873 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Poole, R. C. & Halestrap, A. P. N-terminal protein sequence analysis of the rabbit erythrocyte lactate transporter suggests identity with the cloned monocarboxylate transport protein MCT1. Biochem. J. 303, 755–759 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Dimmer, K. S., Friedrich, B., Lang, F., Deitmer, J. W. & Broer, S. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J. 350, 219–227 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Manning Fox, J. E., Meredith, D. & Halestrap, A. P. Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J. Physiol. 529 Pt. 2, 285–293 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Pinheiro, C. et al. Role of monocarboxylate transporters in human cancers: state of the art. J. Bioenerg. Biomembr. 44, 127–139 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Miranda-Goncalves, V. et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 15, 172–188 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Kirk, P. et al. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J. 19, 3896–3904 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Biswas, C. et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res. 55, 434–439 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Murray, C. M. et al. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nature Chem. Biol. 1, 371–376 (2005).

    CAS  Google Scholar 

  103. 103

    Schneiderhan, W. et al. CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut 58, 1391–1398 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Le Floch, R. et al. Growth inhibition of glycolytic tumors by targeting basigin/lactate-H+ symporters (MCTs): metformin sensitizes MCT inhibition. Cancer Res. 72 (Suppl. 8), 3225 (2012).

    Google Scholar 

  105. 105

    Fang, J. et al. The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol. Pharmacol. 70, 2108–2115 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Wahl, M. L. et al. Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol. Cancer Ther. 1, 617–628 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Becker, H. M., Hirnet, D., Fecher-Trost, C., Sultemeyer, D. & Deitmer, J. W. Transport activity of MCT1 expressed in Xenopus oocytes is increased by interaction with carbonic anhydrase. J. Biol. Chem. 280, 39882–39889 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Klier, M. et al. Transport activity of the high-affinity monocarboxylate transporter MCT2 is enhanced by extracellular carbonic anhydrase IV but not by intracellular carbonic anhydrase II. J. Biol. Chem. 286, 27781–27791 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Gallagher, S. M., Castorino, J. J. & Philp, N. J. Interaction of monocarboxylate transporter 4 with beta1-integrin and its role in cell migration. Am. J. Physiol. Cell Physiol. 296, C414–C421 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Gallagher, S. M., Castorino, J. J., Wang, D. & Philp, N. J. Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 67, 4182–4189 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Forgac, M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nature Rev. Mol. Cell Biol. 8, 917–929 (2007).

    CAS  Google Scholar 

  112. 112

    Fais, S. Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J. Intern. Med. 267, 515–525 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Martinez-Zaguilan, R., Lynch, R. M., Martinez, G. M. & Gillies, R. J. Vacuolar-type H+-ATPases are functionally expressed in plasma membranes of human tumor cells. Am. J. Physiol. 265, C1015–C1029 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Martinez-Zaguilan, R. et al. pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochem. Pharmacol. 57, 1037–1046 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Xu, J. et al. Expression and functional role of vacuolar H+-ATPase in human hepatocellular carcinoma. Carcinogenesis 33, 2432–2440 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Lim, J. H. et al. ATP6V0C competes with von Hippel-Lindau protein in hypoxia-inducible factor 1α (HIF-1α) binding and mediates HIF-1α expression by bafilomycin A1. Mol. Pharmacol. 71, 942–948 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Klionsky, D. J., Elazar, Z., Seglen, P. O. & Rubinsztein, D. C. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 4, 849–950 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Yamamoto, A. et al. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 23, 33–42 (1998).

    CAS  PubMed  Google Scholar 

  119. 119

    Mattsson, J. P., Vaananen, K., Wallmark, B. & Lorentzon, P. Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H+-translocating ATPases. Biochim. Biophys. Acta 1065, 261–268 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Moriyama, Y., Patel, V., Ueda, I. & Futai, M. Evidence for a common binding site for omeprazole and N-ethylmaleimide in subunit A of chromaffin granule vacuolar-type H+-ATPase. Biochem. Biophys. Res. Commun. 196, 699–706 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Udelnow, A. et al. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PLoS ONE 6, e20143 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    De Milito, A. et al. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int. J. Cancer 127, 207–219 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    De Milito, A. et al. Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res. 67, 5408–5417 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Marino, M. L. et al. Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. Cell Death Dis. 1, e87 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Marino, M. L. et al. Autophagy is a protective mechanism for human melanoma cells under acidic stress. J. Biol. Chem. 287, 30664–30676 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Swietach, P., Hulikova, A., Patiar, S., Vaughan-Jones, R. D. & Harris, A. L. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS ONE 7, e35949 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Wojtkowiak, J. W. et al. Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Res. 72, 3938–3947 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Efeyan, A., Zoncu, R. & Sabatini, D. M. Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18, 524–533 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Russnak, R., Konczal, D. & McIntire, S. L. A family of yeast proteins mediating bidirectional vacuolar amino acid transport. J. Biol. Chem. 276, 23849–23857 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Mazure, N. M. & Pouyssegur, J. Hypoxia-induced autophagy: cell death or cell survival? Curr. Opin. Cell Biol. 22, 177–180 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Kimura, T., Takabatake, Y., Takahashi, A. & Isaka, Y. Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res. 73, 3–7 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Roos, A. & Boron, W. F. Intracellular pH. Physiol. Rev. 61, 296–434 (1981). The most extensive review on pH i regulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Voegtlin, C. & Kahler, H. The estimation of the hydrogen-ion concentration of the tissues in living animals. Science 75, 362–364 (1932). The first measurements of tumour pH e using electrodes.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Gerweck, L. E. & Seetharaman, K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 56, 1194–1198 (1996). An important summary of human patient tumour and normal tissue pH i and pH e measurements.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Vaupel, P., Kallinowski, F. & Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Wike-Hooley, J. L., Haveman, J. & Reinhold, H. S. The relevance of tumour pH to the treatment of malignant disease. Radiother. Oncol. 2, 343–366 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Lutz, N. W., Le Fur, Y., Chiche, J., Pouyssegur, J. & Cozzone, P. J. Quantitative in-vivo characterization of intracellular and extracellular pH profiles in heterogeneous tumors: a novel method enabling multiparametric pH analysis. Cancer Res. http://dx.doi.org/10.1158/0008-5472.CAN-13-076 (2013).

  140. 140

    Gillies, R. J., Raghunand, N., Karczmar, G. S. & Bhujwalla, Z. M. MRI of the tumor microenvironment. J. Magn. Reson. Imag. 16, 430–450 (2002).

    Google Scholar 

  141. 141

    Pouyssegur, J. et al. in Cancer Cells (eds Feramisco, J., Ozanne, B. & Stiles, C.) 409–415 (Cold Spring Harbor, 1985).

    Google Scholar 

  142. 142

    Rotin, D., Steele-Norwood, D., Grinstein, S. & Tannock, I. Requirement of the Na+/H+ exchanger for tumor growth. Cancer Res. 49, 205–211 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Rotin, D., Robinson, B. & Tannock, I. F. Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors. Cancer Res. 46, 2821–2826 (1986).

    CAS  PubMed  Google Scholar 

  144. 144

    Rotin, D., Wan, P., Grinstein, S. & Tannock, I. Cytotoxicity of compounds that interfere with the regulation of intracellular pH: a potential new class of anticancer drugs. Cancer Res. 47, 1497–1504 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Newell, K. J. & Tannock, I. F. Reduction of intracellular pH as a possible mechanism for killing cells in acidic regions of solid tumors: effects of carbonylcyanide-3-chlorophenylhydrazone. Cancer Res. 49, 4477–4482 (1989). This series of papers from Tannock's group (references 142–145) provided much of the early information regarding pH i disruption and cancer cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Boron, W. F. Regulation of intracellular pH. Adv. Physiol. Educ. 28, 160–179 (2004).

    PubMed  PubMed Central  Google Scholar 

  147. 147

    Binggeli, R. & Cameron, I. L. Cellular potentials of normal and cancerous fibroblasts and hepatocytes. Cancer Res. 40, 1830–1835 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Gatenby, R. A. & Gawlinski, E. T. A reaction-diffusion model of cancer invasion. Cancer Res. 56, 5745–5753 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Gatenby, R. A. & Gillies, R. J. A microenvironmental model of carcinogenesis. Nature Rev. Cancer 8, 56–61 (2008).

    CAS  Google Scholar 

  150. 150

    Rofstad, E. K., Mathiesen, B., Kindem, K. & Galappathi, K. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res. 66, 6699–6707 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Svastova, E. et al. Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J. Biol. Chem. 287, 3392–3402 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Estrella, V. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 73, 1524–1535 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Robey, I. F. et al. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 69, 2260–2268 (2009). This study showed complete inhibition of spontaneous metastases through NaHCO 3 buffering.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Silva, A. S., Yunes, J. A., Gillies, R. J. & Gatenby, R. A. The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Res. 69, 2677–2684 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Ibrahim-Hashim, A. et al. Systemic buffers inhibit carcinogenesis in TRAMP mice. J. Urol. 188, 624–631 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Chan, D. A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med. 3, 94ra70 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Elorza, A. et al. HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol. Cell 48, 681–691 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Tennant, D. A., Duran, R. V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer 10, 267–277 (2010).

    CAS  Google Scholar 

  159. 159

    Pollak, M. Targeting oxidative phosphorylation: why, when, and how. Cancer Cell 23, 263–264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Gottschalk, S., Anderson, N., Hainz, C., Eckhardt, S. G. & Serkova, N. J. Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. Clin. Cancer Res. 10, 6661–6668 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23, 302–315 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Shackelford, D. B. et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995). The first cloning and description of the HIF1α and HIF1β subunits.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).

    PubMed  Google Scholar 

  165. 165

    Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Trastour, C. Expression of Hypoxic and Metabolic Biomarkers in Breast Cancer. Thesis, Univ. Nice Sophia-Antipolis (2010).

    Google Scholar 

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Acknowledgements

Research in the authors' laboratory is financed by European Community (EU7-METOXIA) and French agencies and associations: the Agence Nationale de la Recherche, Ligue Nationale Contre le Cancer (Equipe Labellisée), Institut National du Cancer and grants from the Fondation ARC pour la Recherche sur le Cancer (to S.K.P. and J.C.).

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Glossary

Cytostatic

Pertaining to cytostasis, which is basic cellular function without progression through the cell cycle.

H+ dynamics

The interaction between extracellular pH and intracellular pH with respect to acid–base movement between the two compartments and their subsequent cellular effects.

Transport metabolon

A group of enzymatic proteins that interact to achieve a more efficient exchange of metabolites.

Monocarboxylates

Molecules that have one carboxylate group in their structure and require facilitated transport across the plasma membrane; for example, lactate and pyruvate.

Synthetic lethality

The process of targeting multiple proteins and regulatory systems, by which the combined therapy will induce cell death.

Chronic autophagy

Long-term cellular adaptation towards consumption of cellular components.

Ragulator complex

A multiprotein complex that is responsible for the translocation of mTOR complex 1 to the lysosomal surface.

Metabolic dormancy

Suppression of cellular metabolism to provide just the minimal energy required to maintain cytostasis.

Ionophores

Molecules that facilitate the movement of ions across the cell membrane, normally by the formation of pores.

Nernst equilibrium potential

A mathematical formula that describes the equilibrium state of ions between two compartments based on the concentration and electric gradients that exist in the system.

pKa

The acid dissociation constant that indicates the relative strength of a given acid in solution.

Evolutionary game theory

The application of strategic game theory mathematical modelling to the evolutionary progression of a biological system.

Unfolded protein response

A stress response within the cell that responds to misfolded proteins and initiates a cascade that leads to apoptotic cell death.

Metabolic catastrophe

When cellular metabolism is disrupted severely enough to prevent energy (ATP) production and the cell consequently perishes.

ATP crisis

A state in which the cell does not produce enough ATP to meet its energetic demands for survival.

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Parks, S., Chiche, J. & Pouysségur, J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer 13, 611–623 (2013). https://doi.org/10.1038/nrc3579

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