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Glycogen Protects Clear‐Cell Carcinoma: dependence on the hypoxia inducible pathway and a potential therapeutic role for glycogenolysis inhibitors.
Author(s) -
Parker Glendon J
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.678.10
Subject(s) - glycogenolysis , glycogen , glycolysis , glycogenesis , glycogen phosphorylase , glycogen synthase , cancer research , hypoxia (environmental) , glycogen branching enzyme , chemistry , cancer cell , medicine , endocrinology , biology , metabolism , cancer , oxygen , organic chemistry
Compromised oxygen delivery is a major feature of solid tumor biology. Carcinoma metabolism up regulates glycolysis to produce ATP in an oxygen independent manner. As a result, carcinoma cells are highly dependent on glucose delivery and availability. Clear‐cell carcinomas, a histologic variant present in many cancer types, have distinctive, large intracellular reserves of glycogen, the polymeric form of glucose. We hypothesized that glucose mobilized from glycogen reserves would protect renal cell carcinoma (RCC) from nutrient and oxygen deprivation. We induced glycogenosis in Caki‐2 human renal cell carcinoma cells with desferrioxamine (DFO), an activator of the hypoxia‐inducible factor (HIF) pathway. The induced glycogenosis was shown to be HIF‐dependent using RNAi targeted against HIF‐1alpha (p < 0.01). The accumulated glycogen reserves were responsive to metabolic status (p < 0.05). Mobilization of glycogen reserves protect Caki‐2 cells incubated with azide in glucose‐free media, whereas non‐glycogenotic Caki‐2 cells started to lose viability after 4 h (p < 0.05). Inhibition of glycogen phosphorylase removed the protective effect of glycogenosis (p < 0.05). This demonstrates that glycogen protects RCC and that inhibition of glycogenolysis would complement anti‐angiogenic compounds, which restrict oxygen delivery and increase dependence on glycogen metabolism.