P38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.

ABSTRACT: KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here, we report that p38γ MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38γ interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38γ increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38γ decreased PFKFB3 and GLUT2 expression. p38γ phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38γ decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice.

SUBMITTER: Wang F 

PROVIDER: S-EPMC9358694 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature