Dynamic Reprograming of Tumor Cell Metabolism by Hypoxic Microenvironments

Dynamic reprograming of tumor cell metabolism by hypoxic microenvironments

In response to genetic alterations and signals from the microenvironment, tumor cells transform their metabolism to survive and fuel their aggressive growth.  Quantitative, systems-based approaches using isotopic tracers and mass spectrometry are effective tools for the identification of pathways and fluxes specifically utilized by cancer cells.  Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty acid synthesis and protein acetylation, and in the conventional view of metabolism, AcCoA is thought to be generated primarily from glucose carbon via the citrate shuttle.  Using ¹³C Metabolic Flux Analysis (MFA) we show that human tumor cells employ reductive metabolism of alpha-ketoglutarate (aKG) to synthesize AcCoA for lipid synthesis.  This reaction is catalyzed by isocitrate dehydrogenase 1 (IDH1), which competes for substrate with aKG-dependent oxygenases in the cytosol.  Furthermore, cancer cell lines grown under hypoxia rely almost entirely on the reductive carboxylation of glutamine-derived aKG for lipogenesis.  This metabolic “switch” is mediated, in part, by hypoxia inducible factor a (HIFa) stabilization and also triggered by oncogenic loss of the von Hippel-Lindau tumor suppressor protein.  These results fundamentally alter our understanding of cell metabolism and identify a critical role of O₂ in regulating glutamine utilization in tumor cells.