Prognostic and immunological significance of key gluconeogenesis regulators, PCK1 and PCK2, in human cancers especially kidney renal clear cell carcinoma: Insights from pan-cancer analysis, PCKs signature construction, and in vitro experiments

Abstract

BackgroundMetabolic reprogramming is a significant feature of tumor cells, and targeting metabolic pathways has become a viable strategy for cancer therapy. Gluconeogenesis is essential to glucose metabolism, with phosphoenolpyruvate carboxykinase 1 (PCK1) and phosphoenolpyruvate carboxykinase 2 (PCK2) as key enzymes. The roles of PCK1 and PCK2 in various cancers remain unclear. MethodsWe conducted a comprehensive overview of PCK1 and PCK2 in human cancers, assessing their expression and association with prognosis, tumor immunity, and drug sensitivity. Prognostic relevance, synergistic effects, and potential binding activity were also investigated. ResultsPCK1 and PCK2 expression were downregulated in most cancer types, displaying heterogeneity between and within tumors. Their effects on prognosis were bidirectional with synergistic interactions. PCK1 and PCK2 expression correlated with immune subtypes, tumor mutational burden, microsatellite instability, immune checkpoints, and immune cell infiltration. Expression variation was observed in diverse or specific tumor types. The association with drug sensitivity indicated the potential for targeting PCK1 and PCK2 to improve drug resistance. A PCKs signature was constructed respectively, confirming their pro-oncogenic role in adrenocortical carcinoma and oncogenic role in kidney renal clear cell carcinoma (KIRC). Experimental validation identified their significant impact on KIRC, with some binding molecules identified through drug prediction and molecular docking. ConclusionsOur study revealed the key roles of PCK1 and PCK2 in tumorigenesis, metastasis, tumor immunity, and metabolic activity, suggesting their potential as therapeutic targets, particularly for KIRC.