Glutamine synthetase mediates sorafenib sensitivity in beta-catenin-active hepatocellular carcinoma cells

초록

The gene encoding beta-catenin is frequently mutated in hepatocellular carcinoma cells. While the oncogenicity of beta-catenin has been extensively studied, beta-catenin's role in hepatocellular carcinoma tumor metabolism is currently less well understood. In this study, we found that beta-catenin regulates the expression of glutamine synthetase and triggers a series of metabolic changes leading to induction of autophagy in hepatocellular carcinoma cells. beta-Catenin-active Hep3B and HepG2 cells exhibited higher basal levels of autophagic activity than did beta-catenin wild-type cells. We also found that autophagy in beta-catenin-active cells was mediated by glutamine synthetase, as silencing of glutamine synthetase significantly reduced autophagic activity. We also showed that beta-catenin-active hepatocellular carcinoma cells were more sensitive to sorafenib than were beta-catenin wild-type cells. Our results demonstrated that glutamine synthetase-mediated autophagy explains the high sensitivity of beta-catenin-active hepatocellular carcinoma cells to sorafenib. Our results highlight the importance of glutamine metabolism in the regulation of autophagy in hepatocellular carcinoma cells. More importantly, our study unravels the molecular mechanisms leading to sorafenib sensitivity in hepatocellular carcinoma.

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