Hypoxia-induced metabolic shifts in cancer cells: moving beyond the Warburg effect

Abstract

Hypoxia has been recognized to play a role in promoting the invasive and metastatic behaviour of cancer cells. Largely via the transcription factor, hypoxia-induced factor 1, hypoxia exerts significant effects on cellular metabolism, with numerous downstream consequences. Energetically there is a significant shift away from oxidative phosphorylation in mitochondria towards glycolysis, a state also involved in the 'Warburg effect'. The proteins involved in mediating the altered metabolic pathways seen in tumour cells thus represent new targets for potential therapeutic intervention. Hypoxia has been associated with the development of aggressive phenotypes in cancer cells, and can be accompanied by changes in carbohydrate and lipid metabolism that impact tumour cell proliferation, adhesion, and angiogenesis. Herein, we examine glycolytic and other less investigated metabolic pathways in relation to cancer and hypoxia, with a focus on emerging tools for large-scale metabolite profiling ('metabolomics'). Metabolomic technologies permit the measurement of a wide range of metabolites in an untargeted manner, however, to date, this technology has been relatively under utilized for studying cellular responses to hypoxia. We detail some of the common experimental approaches employed in metabolomics experiments, including nuclear magnetic resonance and new mass spectrometry-based methods of analysis. Selected examples of the application of these technologies to the study of metabolic alterations brought about by hypoxia are provided, particularly as they relate to energy, carbohydrate, and lipid metabolism. Finally, the potential for therapeutic targeting of metabolic processes activated by hypoxia is presented.