PP4R1 promotes glycolysis and gallbladder cancer progression through facilitating ERK1/2 mediated PKM2 nuclear translocation

Gallbladder cancer (GBC) is a common solid tumor of the biliary tract with a high mortality rate and limited curative benefits from surgical resection. Here, we aimed to elucidate the pathogenesis of GBC from the perspective of molecular mechanisms and determined that protein phosphatase 4 regulator subunit 1 (PP4R1) is overexpressed in GBC tissues and contributes to poor prognosis. Through a series of in vitro and in vivo experiments, we demonstrated that PP4R1 overexpression improved tumorigenesis in GBC cells. Further mechanistic exploration revealed that PP4R1 directly interacts with pyruvate kinase-M2 (PKM2), a key regulator of glycolysis. PP4R1 promotes the extracellular signal-related kinase 1 and 2 (ERK1/2)-mediated PKM2 nuclear translocation, thereby participating in the regulation of tumor glycolysis. Interestingly, we determined that PP4R1 strengthens the interaction between ERK1/2 and PKM2. Furthermore, PP4R1 enhanced the suppressive effects of the ERK inhibitor SCH772984 on GBC. In conclusion, our data showed that PP4R1 is a promising biomarker associated with GBC and confirmed that PP4R1 regulates PKM2-mediated tumor glycolysis, which provides a metabolic growth advantage to GBC cells, thereby promoting GBC tumor growth and metastasis¹.