Abstract
Clear cell renal cell carcinoma (ccRCC) is a major subtype of renal cell carcinoma and characterized by metabolic reprogramming, especially glycolysis. Neurexophilin 4 (NXPH4) is associated with malignancy of several cancers. However, its function in ccRCC remains unclear. In the current study, several online bioinformatics databases confirmed that NXPH4 was highly expressed in ccRCC tissues and was correlated with poor prognosis in patients with ccRCC. Notably, inhibition of NXPH4 suppressed cell viability, invasion and migration of ccRCC cells, and promoted cell apoptosis; while its overexpression produced the opposite effects. Further online database revealed a positive correlation between NXPH4 expression and glycolysis-related genes LDHA and HK2 in ccRCC tissues. Suppression of NXPH4 obviously decreased protein expression of LDHA and HK2 in ccRCC cells. Importantly, knockdown of NXPH4 attenuated glycolysis by inhibiting glucose uptake, lactate, ATP levels, extracellular acidification rate (ECAR) and increasing oxygen consumption rate (OCR); however, NXPH4 up-regulation promoted glycolysis. Intriguingly, the pro-tumor effects of NXPH4 were reversed by the glycolysis antagonist 2-DG. Additionally, NXPH4 elevation activated the PI3K/AKT pathway, while blocking this pathway significantly offset NXPH4-driven glycolysis, viability, invasion and migration. Collectively, NXPH4 may contribute to cancer cell growth and metastatic potential in ccRCC by activating the PI3K/AKT-evoked glycolysis, supporting it as a promising therapeutic target for ccRCC.