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Activation of the hypoxia pathway and glycogen metabolism

Renal cell carcinoma cells (RCCC) are the cause of around 90% of kidney cancer. This cancer is distinctive in that the hypoxia pathway is dysregulated, often through the absence of von Hippl‐ Lindau protein, and it has excessive levels of glycogen, which leads to the distinctive “clear‐cell” carcinoma histological phenotype. We hypothesized that the two distinctive features of RCCC are causally linked. To test this we treated Caki‐2 cells, an RCCC cell line, for 30 hours with conditions that activated the hypoxia pathway: including: deferoxamine or DFO (100 μM, 300 μM), a hypoxia chamber and cobalt chloride (CoCl2, 100 μM). Deferoxamine (100 μM, 300 μM), which activates PHD by depleting intracellular Fe2+, and the hypoxia chamber treatment, resulted in significantly higher levels of glycogen (control = 1.5 ± 0.5 μg glucose, hypoxia = 7.4 ± 1.1 μg glucose (p < 0.001), 100μM DFO = 5.9 ± 1.6 μg glucose (p < 0.01), 300μM DFO = 6.1 ± 1.7 μg glucose (p < 0.01); n = 4). Treatment with RNAi oligonucleotides targeted to HIF‐1α, or with exogenous iron, eliminated the ability of deferoxamine to induce glycogenolysis. This illustrates a possible casual link between hypoxia and glycogen accumulation.