Abstract
Abstract Wnt/β-catenin signaling has been known to be involved in many cellular processes including cell proliferation, migration, and survival. Aberrant activation of Wnt/β-catenin signaling has been widely reported in many cancers and associated with poor outcome after treatments. However, activation of Wnt/β-catenin signaling in hepatocellular carcinoma (HCC) has been known to be significantly associated with favorable outcome. In this study, we identified 82 genes as a β-catenin signature by analyzing expression data from tumor tissues of patients with HCC and liver tissues from active β-catenin mutant transgenic mice. HCC patients with the β-catenin signature have significantly better prognosis in both overall survival and recurrence-free survival than those without the signature. Further analysis of β-catenin signature revealed over-expression of glutamine synthetase (GS), liver-specific β-catenin target gene, and shift of glutamine metabolism. Cell growth rate were highly dependent on GS expression levels. Cell proliferation rate was increased by GS knockdown using shRNAs but decreased by GS overexpression in HCC cell lines. Intracellular glutamate concentrations were severely decreased by GS overexpression. GS overexpression in HCC cells also led to decrease intracellular α-ketoglutarate levels impeding TCA cycle, and intracellular glutathione levels accumulating high reactive oxygen species (ROS). In conclusion, we found GS up-regulation in HCC cells inhibited cell growth by glutamate depletion and thereby lower anaplerotic metabolic activity and higher ROS levels. Our results present molecular mechanisms for the favorable outcome in HCC patients with CTNNB1 mutations and importance of glutamine metabolism in cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5142. doi:1538-7445.AM2012-5142
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