Vaccinia-related Kinase 2 Confers Pancreatic Cancer with Gemcitabine Resistance Through TPI1-driven Aerobic Glycolysis

Gemcitabine(GEM)-based chemotherapy is considered the first-line regimen for pancreatic cancer(PC), but the poor responsiveness and chemoresistance greatly limit its application. Metabolic reprogramming, especially aerobic glycolysis, which is regulated by glycolytic enzymes, is closely associated with the malignant behavior of PC. Recently, triosephosphate isomerase 1(TPI1), as a key glycolytic enzyme involved in glycolysis, was reported to be increased in GEM-treated PC patients with poor outcome whereas the mechanism remains unclear. In this study, we identified vaccinia-related kinase 2 (VRK2), a serine/threonine protein kinase, which was upregulated in GEM-resistant PC cells and conferred GEM resistance by promoting TPI1-driven aerobic glycolysis. Further studies showed that phosphorylation and nuclear translocation of the transcriptional factor SP1 induced by VRK2 contributed to the interaction of SP1 with the promoter region of TPI1 and thus enhanced the transcriptional activity of TPI1. Taken together, our findings uncover a novel role for VRK2 in modulating glycolytic reprogramming and GEM-resistance, which implicates VRK2 as a potential therapeutic target in PC.