Association of phosphoenolpyruvate carboxykinase 1 protein kinase activity-dependent sterol regulatory element-binding protein 1 activation with prognosis of oesophageal carcinoma. (January 2021) - Shao, Fei
Abstract: Background: Metabolic enzymes have non-canonical functions and play vital roles in the regulation of various cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenic enzyme, was recently identified as an AKT-dependent protein kinase and promoted sterol regulatory element-binding protein 1 (SREBP1)–dependent lipogenesis. However, association of this protein kinase activity of PCK1 with progression of oesophageal squamous cell carcinoma (ESCC) is unclear. Methods: We examined 200 ESCC patient samples and prognosis using immunohistochemistry, multivariate Cox regression and Kaplan–Meier Plot analyses. Results: We show that the expression levels of AKT pS473, AKT-regulated PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151 and nuclear SREBP1 were higher in analysed 200 human ESCC specimens than in their adjacent non-tumour tissues; the expression levels of these proteins were significantly and positively correlated with each other in tumour specimens. In addition, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151 and SREBP1 were associated with the tumour, node and metastasis stage and progression in ESCC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 or nuclear SREBP1 were positively correlated with poor prognosis in patients with ESCC, and the combined expression values of PCK1 pS90, INSIG1 pS207/INSIG2 pS151 and nuclear SREBP1 had a better prognostic value than that of each individual protein expression value and was an independent prognostic marker for ESCC. Conclusion: These findings reveal the role of PCK1 protein kinase activity-dependent SREBP1 activation in ESCC progression. The regulation of SREBP1 by AKT activation-dependent PCK1 protein kinase activity may provide the potential for the diagnosis and treatment of human ESCC. Highlights: AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151 and active sterol regulatory element-binding protein 1 (SREBP1) are high in oesophageal squamous cell carcinoma (ESCC). The levels of these markers are positively correlated with each other in ESCC. The levels of these markers are positively associated with ESCC progression. The combined value of phosphoenolpyruvate carboxykinase 1, INSIG1/2 and SREBP1 is a prognostic marker for ESCC.