Glycogen phosphorylase inhibition activates intrinsic apoptosis pathway and potentiates multi‐kinase inhibitors in liver cancer cells

Abstract

Hepatocellular carcinoma (HCC) is one of the leading cancers in terms of incidence and mortality. There are fewer chemotherapies with HCC with a low survival rate. One of the prominent features of cancer is metabolic reprogramming and thus metabolic proteins are viable targets for cancer treatment. Glycogen is a polymer of glucose, which acts as a reservoir of energy in mammalian cells. The levels of glycogen have been found to correlate with biological processes in cancer cells, however, the role of glycogen metabolism in carcinogenesis, cancer cell growth, metastasis, and chemoresistance is not completely understood. Thus, we studied the cellular processes involved in the inhibition of glycogen metabolism in HCC. Pharmacological inhibition of glycogen phosphorylase (GP) by CP‐91149, a rate‐limiting enzyme in glycogen catabolism, led to a decrease in HepG2 viability. GP inhibition induced the intrinsic apoptosis pathway causing HepG2 cell death. This process was accompanied by mitochondrial dysfunction and autophagic adaptations, whereas endoplasmic reticulum stress, necrosis, and necroptosis were not involved. In addition, GP inhibition potentiated the effects of the multi‐kinase inhibitors sorafenib and regorafenib, which are key drugs in advanced‐stage HCC therapy. Our study provides mechanistic insights into cell death by perturbations of glycogen metabolism and identifies GP inhibition as a potential cancer pharmacotherapy target.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.