Metabolic alterations and mitochondrial dysfunction underlie hepatocellular carcinoma cell death induced by a glycogen metabolic inhibitor

by Selleckchem | Mar 31 2023

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. There is an urgent need for new targets to treat HCC due to limited treatment options and drug resistance. Many cancer cells are known to have high amount of glycogen than their tissue of origin and inhibition of glycogen catabolism induces cancer cell death by apoptosis. To further understand the role of glycogen in HCC and target it for pharmacotherapy, we studied metabolic adaptations and mitochondrial function in HepG2 cells after pharmacological inhibition of glycogen phosphorylase (GP) by CP-91149 (CP). GP inhibition increased the glycogen levels in HepG2 cells without affecting overall glucose uptake. Glycolytic capacity and importantly glycolytic reserve decreased significantly. Electron microscopy revealed that CP treatment altered mitochondrial morphology leading to mitochondrial swelling with less defined cristae. A concomitant decrease in mitochondrial oxygen consumption and mitochondria-linked ATP generation was observed. Metabolomics and enzyme activity / expression studies showed a decrease in the pentose phosphate pathway. In addition, CP treatment decreased the growth of HepG2 3D tumor spheroids in a dose- and time-dependent manner. Taken together, our study provides insights into metabolic alterations and mitochondrial dysfunction accompanying apoptosis in HepG2 cells upon GP inhibition. Our study can aid in the understanding of the mechanism and development of metabolic inhibitors to treat HCC.

Comments：

The studyprovides valuable insights into the potential role of glycogen metabolism in the development and progression of hepatocellular carcinoma (HCC), and its inhibition as a potential therapeutic strategy. Specifically, the study investigated the effects of pharmacological inhibition of glycogen phosphorylase (GP) by CP-91149 (CP) on metabolic adaptations and mitochondrial function in HepG2 cells, which are commonly used as a model of HCC.

The results of the study showed that GP inhibition increased glycogen levels in HepG2 cells without affecting overall glucose uptake, indicating that glycogen metabolism is an important source of energy for HCC cells. Importantly, inhibition of GP led to a significant decrease in glycolytic capacity and glycolytic reserve, which are crucial for cancer cell survival and proliferation. The study also revealed that CP treatment altered mitochondrial morphology, leading to mitochondrial swelling and decreased mitochondrial function, as evidenced by a decrease in oxygen consumption and ATP generation. This mitochondrial dysfunction was accompanied by a decrease in the pentose phosphate pathway, which is important for the production of nucleotides and other cellular components.

Importantly, the study also showed that inhibition of GP by CP decreased the growth of HepG2 3D tumor spheroids in a dose- and time-dependent manner, suggesting that targeting glycogen metabolism could be a promising strategy for the treatment of HCC. Overall, the study provides important insights into the metabolic alterations and mitochondrial dysfunction accompanying apoptosis in HepG2 cells upon GP inhibition, and could aid in the development of metabolic inhibitors as potential therapies for HCC.