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Keywords:

  • acidosis;
  • carbonic anhydrases;
  • energy production;
  • glycolysis;
  • hypoxia-inducible factor;
  • monocarboxylate transporters;
  • Na+/H+ exchanger;
  • oncogenes activation;
  • pH homeostasis;
  • tumour microenvironment

Abstract

  • • 
    Introduction
  • • 
    Intracellular pH regulation controls energy balance and cell proliferation: chemical and biological proof of principle
    • - 
      Chemical proof of principle
    • - 
      Biological proof of principle: the role of the Na+/H+ exchanger-1
  • • 
    Oncogene activation and transformation cause acidosis
    • - 
      Warburg effect (aerobic glycolysis)
    • - 
      Inhibition of tumour suppressor genes and oncogene activation drive the ‘Warburg effect’ and cause acidosis
    • - 
      Neoplastic transformation drives intracellular alkalinization and extracellular acidification through the activation and up-regulation of pHi-regulating systems
  • • 
    Hypoxia promotes acidosis by shifting from oxidative phosphorylation to glycolytic metabolism
    • - 
      HIF mediates cellular adaptation to low oxygen availability
    • - 
      HIF-induced metabolic reprogramming in response to tumour hypoxia causes acidosis
    • - 
      Acidosis may affect HIF-α stabilization and on HIF-induced gene regulation
  • • 
    Hypoxia enhances the expression and activity of pHi-regulating systems to promote cell survival and invasion
    • - 
      Hypoxia increases NHE-1 expression and activity
    • - 
      The hypoxia-induced membrane-associated carbonic anhydrases are key enzymes involved in pH homeostasis, cell survival and migration in a hypoxic/acidic microenvironment
      • - 
        CAIX regulation and expression
      • - 
        CAXII regulation and expression
      • - 
        The activity and functions of CAIX and CAXII
    • - 
      The hypoxia-induced monocarboxylate transporter MCT4, the constitutively expressed MCT1 and their chaperone CD147 are key plasma-membrane proteins involved in pH regulation, energy balance, tumour progression and metastasis
      • - 
        MCT regulation, expression, structure and implication of their chaperone CD147
      • - 
        The MCT1, MCT4 and CD147 activity and functions
  • • 
    Strategies taking advantage of changes in the oxygen level, energy balance and pH homeostasis to target primary tumours and metastases
    • - 
      Decreasing the pHi of hypoxic cells of the primary tumour by inhibiting key pHi-regulating systems to collapse ATP production
    • - 
      Increasing pHo and the extracellular buffering capacity in targeting metastasis and reducing multidrug resistance
  • • 
    Conclusion

Maintenance of cellular pH homeostasis is fundamental to life. A number of key intracellular pH (pHi) regulating systems including the Na+/H+ exchangers, the proton pump, the monocarboxylate transporters, the HCO3 transporters and exchangers and the membrane-associated and cytosolic carbonic anhydrases cooperate in maintaining a pHi that is permissive for cell survival. A common feature of tumours is acidosis caused by hypoxia (low oxygen tension). In addition to oncogene activation and transformation, hypoxia is responsible for inducing acidosis through a shift in cellular metabolism that generates a high acid load in the tumour microenvironment. However, hypoxia and oncogene activation also allow cells to adapt to the potentially toxic effects of an excess in acidosis. Hypoxia does so by inducing the activity of a transcription factor the hypoxia-inducible factor (HIF), and particularly HIF-1, that in turn enhances the expression of a number of pHi-regulating systems that cope with acidosis. In this review, we will focus on the characterization and function of some of the hypoxia-inducible pH-regulating systems and their induction by hypoxic stress. It is essential to understand the fundamentals of pH regulation to meet the challenge consisting in targeting tumour metabolism and acidosis as an anti-tumour approach. We will summarize strategies that take advantage of intracellular and extracellular pH regulation to target the primary tumour and metastatic growth, and to turn around resistance to chemotherapy and radiotherapy.