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Introduction
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Intracellular pH regulation controls energy balance and cell proliferation: chemical and biological proof of principle
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Chemical proof of principle
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Biological proof of ...principle: the role of the Na+/H+ exchanger‐1
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Oncogene activation and transformation cause acidosis
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Warburg effect (aerobic glycolysis)
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Inhibition of tumour suppressor genes and oncogene activation drive the ‘Warburg effect’ and cause acidosis
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Neoplastic transformation drives intracellular alkalinization and extracellular acidification through the activation and up‐regulation of pHi‐regulating systems
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Hypoxia promotes acidosis by shifting from oxidative phosphorylation to glycolytic metabolism
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HIF mediates cellular adaptation to low oxygen availability
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HIF‐induced metabolic reprogramming in response to tumour hypoxia causes acidosis
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Acidosis may affect HIF‐α stabilization and on HIF‐induced gene regulation
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Hypoxia enhances the expression and activity of pHi‐regulating systems to promote cell survival and invasion
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Hypoxia increases NHE‐1 expression and activity
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The hypoxia‐induced membrane‐associated carbonic anhydrases are key enzymes involved in pH homeostasis, cell survival and migration in a hypoxic/acidic microenvironment
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CAIX regulation and expression
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CAXII regulation and expression
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The activity and functions of CAIX and CAXII
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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
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MCT regulation, expression, structure and implication of their chaperone CD147
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The MCT1, MCT4 and CD147 activity and functions
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Strategies taking advantage of changes in the oxygen level, energy balance and pH homeostasis to target primary tumours and metastases
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Decreasing the pHi of hypoxic cells of the primary tumour by inhibiting key pHi‐regulating systems to collapse ATP production
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Increasing pHo and the extracellular buffering capacity in targeting metastasis and reducing multidrug resistance
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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.
Oxygen, a source of life and stress Brahimi-Horn, M. Christiane; Pouysségur, Jacques
FEBS letters,
July 31, 2007, Volume:
581, Issue:
19
Journal Article
Peer reviewed
Open access
Oxygen is an essential element in the survival of complex organisms, however the level of oxygen, low or high, can be a source of stress depending on the biological context. Low levels of oxygen in ...tissues (hypoxia) can be the consequence of a number of pathophysiological conditions including ischemic disorders and cancer while relative, higher levels (hyperoxia) can lead to retinopathy of prematurity. The local oxygen environment and oxygen consumption dictate vascular homeostasis, vaso-proliferation and vaso-cessation, which is deregulated in these diseases through oxygen-dependent growth factors. In this review, we will introduce aspects of the physiology and biology of oxygen partial pressure and the molecular mechanisms implicated in oxygen sensing. We will outline the regulation and function of the key operator in cellular signalling of hypoxia, the transcription factor, hypoxia-inducible factor. In addition, we will focus on cancer cell hypoxia and on its role in driving cell metabolism, pH regulation and survival.
Acidosis of the tumor microenvironment is typical of a malignant phenotype, particularly in hypoxic tumors. All cells express multiple isoforms of carbonic anhydrase (CA), enzymes catalyzing the ...reversible hydration of carbon dioxide into bicarbonate and protons. Tumor cells express membrane-bound CAIX and CAXII that are controlled via the hypoxia-inducible factor (HIF). Despite the recognition that tumor expression of HIF-1alpha and CAIX correlates with poor patient survival, the role of CAIX and CAXII in tumor growth is not fully resolved. To understand the advantage that tumor cells derive from expression of both CAIX and CAXII, we set up experiments to either force or invalidate the expression of these enzymes. In hypoxic LS174Tr tumor cells expressing either one or both CA isoforms, we show that (a) in response to a "CO(2) load," both CAs contribute to extracellular acidification and (b) both contribute to maintain a more alkaline resting intracellular pH (pH(i)), an action that preserves ATP levels and cell survival in a range of acidic outside pH (6.0-6.8) and low bicarbonate medium. In vivo experiments show that ca9 silencing alone leads to a 40% reduction in xenograft tumor volume with up-regulation of ca12 mRNA levels, whereas invalidation of both CAIX and CAXII gives an impressive 85% reduction. Thus, hypoxia-induced CAIX and CAXII are major tumor prosurvival pH(i)-regulating enzymes, and their combined targeting shows that they hold potential as anticancer targets.
Hypoxia and cancer Brahimi-Horn, M Christiane; Chiche, Johanna; Pouysségur, Jacques
Journal of molecular medicine
85, Issue:
12
Journal Article
Peer reviewed
Open access
A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in ...tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.
Hypoxia and energetic tumour metabolism Brahimi-Horn, M Christiane; Bellot, Gregory; Pouysségur, Jacques
Current opinion in genetics & development,
02/2011, Volume:
21, Issue:
1
Journal Article
Peer reviewed
The hypoxia-inducible factor (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumour cells. This transcription factor not ...only favours cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. These include epithelial-mesenchymal transition, angiogenesis, autophagy, and synthesis and storage of lipid and glycogen. HIF-1 also ensures survival by correcting tumour acidosis via increased expression of the carbonic anhydrase CA IX and the lactate/H+ symporter MCT4. The targeting of key HIF-1-mediated steps, responsible for exacerbated glycolysis and pHi-control, and of the ‘guardian of cellular energy’ AMP-kinase should offer novel therapeutic opportunities to fight cancer.
Hypoxia signalling controls metabolic demand Brahimi-Horn, M Christiane; Chiche, Johanna; Pouysségur, Jacques
Current opinion in cell biology,
04/2007, Volume:
19, Issue:
2
Journal Article
Peer reviewed
It has been known for quite some time that cancer cells undergo far-reaching modifications in their metabolism, yet a full understanding of these changes and how they come about remains elusive. Even ...under conditions of plentiful oxygen, cancer cells choose to switch glucose metabolism from respiration to lactic acid formation. The mystery behind the molecular mechanisms of this phenomenon, known as the Warburg effect, is now being unravelled. The reduced respiration rate and increased glucose uptake associated with lactic acid production, and acidosis of the micro-environment, are primarily due to activation of the α/β hypoxia-inducible transcription factor. This distinctive metabolic nature of cancer cells is already being exploited as a diagnostic tool but is yet to be harnessed as a therapeutic intervention.
Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is ...emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N-acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR–ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR–ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy.
The α/β-heterodimeric transcription factor hypoxia-inducible factor (HIF) functions when the oxygen level in tissues is low, i.e. when the tissue microenvironment becomes hypoxic, and is ...non-functional when the level of oxygen is high. Certain pathophysiological conditions such as ischemic disorders and cancer encounter low levels of local tissue oxygenation due to a defective or insufficient vasculature. Highly proliferating tumour cells rapidly form into a mass that becomes located too far from the vasculature to be nourished and oxygenated. Under such conditions HIF activates or represses a vast array of genes that in particular, initiate the formation of new blood vessels and modify metabolism. In this way the tumour mass re-establishes conditions favourable for further proliferation. Interest is being expressed in the direct repression or stimulation of HIF activity, respectively, in the treatment of cancer and of ischemic disorders. The modulation of other HIF-target genes implicated, in particular, in tumour metabolism and intracellular pH control may also prove to be useful in cancer therapy. However, before going further a better understanding of the basics of the HIF signalling pathway is essential. This review will introduce the reader to the molecular mechanisms that regulate HIF and some of the biological consequences of its action, in particular in tumour metabolism, growth and invasion. Approaches to either enforce tumour regression or increase blood vessel formation through the targeting of HIF or its downstream effectors will also be discussed.
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