Hypoxia signalling controls metabolic demand

doi:10.1016/j.ceb.2007.02.003

Current Opinion in Cell Biology

Volume 19, Issue 2, April 2007, Pages 223-229

https://doi.org/10.1016/j.ceb.2007.02.003 Get rights and content

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.

Introduction

Hypoxia, a condition defined as a drop in the oxygen partial pressure (pO₂) from that observed at atmospheric sea-level (normoxia), is encountered to different degrees according to the type of tissue and arises as a direct consequence of insufficient vascularisation in relation to the energy consumption of a given tissue. Hypoxia is also a feature of certain physiological processes, such as embryonic development, and of pathophysiological conditions, such as ischemic diseases (stroke and myocardial infarction) and cancer [1]. A tumour cell mass, developing initially in a vascular environment, can become severely hypoxic as a result of massive expansion distant from the vasculature. To survive this hypoxic stress, tumour cells activate a transcription factor, the hypoxia-inducible factor (HIF), through the stabilization under oxygen-limiting conditions of the α subunit of this α/β heterodimeric factor [2]. HIF in turn rapidly regulates — either positively or negatively — the expression of a wide range of genes [2, 3, 4]. The survival response induces, in particular, a rapid switch to glycolysis and subsequently angiogenesis (the formation of blood vessels from an existing vascular system), thereby re-establishing a nourishing and well-oxygenated environment. The immediate consequence is up-regulation of the glycolytic cascade for transformation of glucose to pyruvate, together with a switch in pyruvate metabolism from transformation through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation in mitochondria to conversion to lactic acid in the cytoplasm [5]. To continue to survive, cells must adjust their intracellular pH to combat the increased generation of lactic acid and do so by activating, in a HIF-dependent manner, several membrane-bound enzymes, exchangers and transporters [6].

This review will first introduce the domain structure, regulation of expression and overall function of HIF and then focus on HIF-induced modulation of the tumour micro-environment through changes in cell metabolism. The notion of exploiting tumour micro-environmental modifications in a therapeutic perspective for cancer will be developed.

Section snippets

Post-translational regulation of the HIF α subunit

The α subunit of HIF exists as three isoforms, numbered from one to three, coded by different genes [1]. The regulation of their stability is similar for each isoform and is highly oxygen dependent. By contrast, the regulation of the β subunit, of which there are two major isoforms involved in the hypoxic response, is independent of oxygen [1]. The very short half-life of the HIFα proteins (five minutes) results from their post-translational hydroxylation by the oxygen, 2-oxoglutarate (2-OG)-

HIF-dependent gene transcription

Thus, under hypoxic conditions the PDH and FIH dioxygenases are inactive and HIFα is stable and available to dimerize with HIFβ through their respective N-terminal domains. The heterodimer then binds site-specific sequences termed hypoxia response elements (HRE) on target genes and, since FIH is inactive, the co-activator CBP/p300 is recruited to the C-TAD for activation of transcription (Figure 1). Although >70 genes are activated in a HIF-dependent manner [2, 4, 11], a substantial number are

Cancer cell metabolism

The metabolism of glucose to CO₂ and water is oxygen dependent and highly energy efficient, with the production of 38 ATP molecules per glucose molecule (Figure 3). Metabolism involves, primarily, cytosolic glucose transformation into pyruvate, and, secondarily, pyruvate catabolism through the TCA cycle and oxidative phosphorylation (OXPHOS) in mitochondria. By contrast, metabolism of glucose via pyruvate to lactic acid — which is sometimes referred to inappropriately as anaerobic glycolysis,

The acidotic tumour micro-environment and cellular pH regulation

One of the major consequences of the tendency towards cytosolic glucose metabolism is acidosis of the tumour micro-environment [37], which might favour an invasive phenotype [38]. A change in the pH of the tumour micro-environment can modulate the activity of proteases that degrade the extracellular matrix, and thus high lactate concentrations have been found to correlate with an increased incidence of metastasis and poor prognosis [39]. Acidosis is due not only to increased lactate but also to

Conclusions

Further understanding of why cancer cells choose to ‘burn’ glucose through cytosolic glucose metabolism instead of mitochondrial respiration, presumably to meet the high energy demands of highly proliferating cells, remains a major challenge in cell biology. The revelation of a non-enzymatic role for certain glycolytic enzymes [29] and for CA IX [49^•] hints at new and unexpected functions that might explain further the primary oxygen-independent glycolytic nature of cancer cells. Since HIF

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We thank G. l’Allemain for critical reading. The laboratory is funded by grants from the Ligue Nationale Contre le Cancer (Equipe labellisée), the Centre A. Lacassagne, the Centre National de la Recherche Scientifique (CNRS), the Ministère de l’Education, de la Recherche et de la Technologie, and the Institut National de la Santé et de la Recherche Médicale (Inserm).

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View full text

Hypoxia signalling controls metabolic demand

Introduction

Section snippets

Post-translational regulation of the HIF α subunit

HIF-dependent gene transcription

Cancer cell metabolism

The acidotic tumour micro-environment and cellular pH regulation

Conclusions

References and recommended reading

Acknowledgements

Blood

Biochem Biophys Res Commun

Cell Signal

Cell Metab

Cancer Lett

Biochem Biophys Res Commun

Nat Rev Cancer

Cell Metab

Oncogene

Science

Mol Cancer Ther

Am J Respir Crit Care Med

Neuro-oncol

The hypoxia-inducible factor and tumor progression along the angiogenic pathway

Int Rev Cytol

Oxygen sensing by HIF hydroxylases

Nat Rev Mol Cell Biol

Targeting HIF-1 for cancer therapy

Nat Rev Cancer

Why do cancers have high aerobic glycolysis?

Nat Rev Cancer

Hypoxia signalling in cancer and approaches to enforce tumour regression

Nature

Regulation of HIF: asparaginyl hydroxylation

Novartis Found Symp

Investigating hypoxic tumor physiology through gene expression patterns

Oncogene

Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivo

EMBO J

Hypoxia-inducible factors, hypoxia, and tumor angiogenesis

Curr Opin Hematol

The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor- 1α

Cancer Res