Inhibition of glycogen catabolism induces intrinsic apoptosis and augments multikinase inhibitors in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the leading cancers in the world in incidence and mortality. Current pharmacotherapy of HCC is limited in the number and efficacy of anticancer agents. Metabolic reprogramming is a prominent feature of many cancers and has rekindled interest in targeting metabolic proteins for cancer therapy. Glycogen is a storage form of glucose, and the levels of glycogen have been found to correlate with biological processes in reprogrammed cancer cells. However, the contribution of glycogen metabolism to carcinogenesis, cancer cell growth, metastasis, and chemoresistance is poorly understood. Thus, we studied the processes involved in the inhibition of glycogen metabolism in HCC cells. Pharmacological inhibition of glycogen phosphorylase (GP), a rate-limiting enzyme in glycogen catabolism, by CP-91149 led to a decrease in HCC cell viability. GP inhibition induced cancer cell death through the intrinsic apoptotic pathway. Mitochondrial dysfunction and autophagic adaptations accompanied this apoptosis process whereas endoplasmic reticulum stress, necrosis, and necroptosis were not major components of the cell death. In addition, GP inhibition potentiated the effects of multikinase inhibitors sorafenib and regorafenib, which are key drugs in advanced-stage HCC therapy. Our study provides mechanistic insights into cell death by perturbation of glycogen metabolism and identifies GP inhibition as a potential HCC pharmacotherapy target.