Cancer metabolic pathways regulated by hypoxia

Metabolic reprogramming in cancer cells provides energy and important metabolites required to sustain tumour proliferation. Hypoxia represents a hostile environment that can encourage these transformations and other adaptive responses that contribute to poor prognosis and resistance to radiation and chemotherapy. Hypoxic signatures associated with worse prognosis were previously derived in different cancer types, and led to the selection of two candidates with potential metabolic implications, namely the mir210-putuative target iron-sulfur scaffold protein ISCU and glycogen phosphorylase (PYGL). Firstly, it was verified that the hypoxia-induced miR-210 targets ISCU. Iron-sulfur clusters represent cofactors for key enzymes involved in Krebs cycle and electron transport chain. Downregulation of ISCU was associated with the induction of reactive oxygen species (ROS) and reduced mitochondrial complex I and aconitase activity, caused a shift to glycolysis in normoxia and enhanced cell survival. This indicates that the induction of a single microRNA, miR-210, can mediate a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation. Secondly, it was found that changes in PYGL expression reflect a characteristic upregulation of glycogen metabolism in hypoxia in both tumour xenografts and in cancer cell lines. More specifically, hypoxia stimulates glycogen accumulation and its utilisation, as well as the concurrent upregulation of several glycogen-metabolizing enzymes such as glycogen synthase (GYS1) and PYGL. PYGL depletion led to glycogen accumulation in hypoxic cells, increased intracellular levels of ROS, and a reduction in proliferation due to a p53-dependent induction of senescence. Furthermore, depletion of PYGL was associated with markedly impaired tumorigenesis in vivo. Finally, metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal functioning of the pentose phosphate pathway. Collectively, this study shows the contribution of two important pathways to the metabolic adaptations induced by hypoxia.