PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA

Background: Suppressed gluconeogenesis and increased glycolysis are common in clear cell renal cell carcinoma (ccRCC). Phosphoenolpyruvate carboxykinase 1 (PCK1) is a ratelimiting gluconeogenesis enzyme. However, the role of PCK1 in tumor metabolism and progression remains unclear. Methods: Artificial modulation of PCK1 (down- and upregulation) in two ccRCC cell lines was performed to explore the role of PCK1 in the glycolytic phenotype and in tumor growth and metastasis in vitro and in vivo. Sixty-two patients with ccRCC underwent F-18-fluorodeoxyglucose (F-18-FDG) positron emission tomography. The levels of PCK1 and lactate dehydrogenase A (LDHA) in ccRCC tissues and peritumor tissues were investigated with immunohistochemistry. The relationships between F-18-FDG accumulation and the expression of PCK1 and LDHA were analyzed. The mechanisms underlying the regulation of LDHA by PCK1 were analyzed using in vitro molecular techniques. Results: PCK1 suppressed ccRCC cell growth and metastasis in vitro and inhibited tumorigenesis in nude mice by blocking the aerobic glycolysis pathway. Clinically, low levels of PCK1 expression were associated with poor prognosis in patients with ccRCC. The expression level of PCK1 was negatively correlated with tumor progression, the LDHA expression level and F-18-FDG accumulation in primary ccRCC tissue. We also demonstrated that PCK1 reduces the stability of LDHA through posttranslational regulation. Finally, we showed that the effects of PCK1 on glucose metabolism, cell proliferation and metastasis are mediated via the inhibition of LDHA. Conclusion: Our study identified a novel molecular mechanism underlying the Warburg effect. PCK1 may serve as a candidate prognostic biomarker, and targeting the PCK1/LDHA pathway might be a new strategy to selectively inhibit tumor metabolism in human ccRCC.