Hypoxia signalling controls metabolic demand
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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