Overexpression of PCK1 Gene Antagonizes Hepatocellular Carcinoma Through the Activation of Gluconeogenesis and Suppression of Glycolysis Pathways

Cellular Physiology and Biochemistry

Yufu Tang¹ 

关键词: Gluconeogenesis;    Glycolysis;    Hepatocellular carcinoma;    Phosphoenolpyruvate carboxykinase 1;   

DOI  :  10.1159/000489811

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims Gluconeogenesis, a reverse process of glycolysis, is suppressed in neoplastic livers. Cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK-C/PCK1, encoded by PCK1) is a step limiting enzyme of gluconeogenesis. The induced expression of the factor is reported to initiate gluconeogenesis process and antagonize hepatocellular carcinoma (HCC). In the current study, the effect of the modulation of PCK1 expression on HCC was assessed. Methods The levels of PCK1 in clinical HCC tissues and different HCC cell lines were investigated with real time quantitative PCR, immunochemistry, and western blotting. Thereafter, the expression of PCK1 gene was induced in two HCC cell lines and the effect of the overexpression on proliferation and migration potentials of HCC cells was detected with CCK-8 assay, flow cytometry, TUNEL staining, and transwell assay. The activities of glycolysis and gluconeogenesis pathways in PCK1-overexpressed HCC cell lines were detected with specific kits to underlie the mechanism by which PCK1 exerted its function. The results of the in vitro experiments were validated with HCC xenograft rat models. Results The expression levels of PCK1 were suppressed in HCC samples and in cells derived from HCC tissues. According to the results of the in vitro assays, the overexpression of PCK1 decreased viability, induced apoptosis, and inhibited migration in both HCC cell lines. The effect was associated with the suppressed glycolysis and the induced gluconeogenesis pathways, represented by the enhanced production of glucose and the limited production of pyruvic acid, lactate, citrate, and malate. The results of the in vitro assays were confirmed in rat models in that the growth rate of solid HCC tumors was reduced in mice transplanted with PCK1-overexpressed HCC cells. Conclusion Findings outlined in the current study demonstrated that activating gluconeogenesis process via PCK1 overexpression was a potential treating strategy against HCC.

【 授权许可】

CC BY-NC-ND