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

Abstract

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.

Metabolomics Study of Dried Ginger Extract on Serum and Urine in Blood Stasis Rats Based on UPLC-Q-TOF/MS

“…Glycolysis is a common way for all organisms to extract energy from glucose, and gluconeogenesis provides a source for new glucose molecules. Glucose is produced from small carbohydrate substrates such as pyruvate, lactic acid, glycerin, and glucose amino acids, and to synthesize glucose from simple starting materials to meet the needs of various tissues [26][27]. And In our study, when BSS occurred, the model group showed signi cant upregulation of pyruvate, suggesting that glucose metabolism disorders may occur.…”

Multi-omics profiling highlights lipid metabolism alterations in pigs fed low-dose antibiotics

“…Additionally, the PCK1 gene, which is involved in both the PPAR signaling pathway and metabolic pathway, is a main control point for the regulation of gluconeogenesis. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet and it has multiple relationships with several metabolic diseases [ 46 , 47 ].…”

Metabolomic Analysis Identifies Glycometabolism Pathways as Potential Targets of Qianggan Extract in Hyperglycemia Rats

“…Glycolysis is a glucose utilization process, which converts glucose into pyruvate or lactate. Gluconeogenesis is opposite to that of glycolysis, which synthesizes glucose from other metabolites like pyruvate, lactate, and glucogenic amino acids (Tang et al, 2018). Glycolysis and gluconeogenesis possess several reversible enzyme-catalyzed reactions and share a series of common intermediates such as glucose-6-phosphate, fructose-6-phosphate, fructose-1, 6bisphosphate, lactate, etc (Sharabi et al, 2015).…”