p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.

Cancer research 2020 Aug 15

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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. PFKFB3 and GLUT2 depended on p38γ to stimulate glycolysis and PDAC growth and p38γ required PFKFB3/S467 to promote these activities. A p38γ inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38γ. Moreover, overexpression of p38γ, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38γ links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38γ and PFKFB3 may be targeted for therapeutic intervention in PDAC. SIGNIFICANCE: These findings show that p38γ links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38γ and PFKFB3. ©2020 American Association for Cancer Research.

Citation

Fang Wang, Xiao-Mei Qi, Ryan Wertz, Matthew Mortensen, Catherine Hagen, John Evans, Yuri Sheinin, Michael James, Pengyuan Liu, Susan Tsai, James Thomas, Alexander Mackinnon, Michael Dwinell, Charles R Myers, Ramon Bartrons Bach, Liwu Fu, Guan Chen. p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis. Cancer research. 2020 Aug 15;80(16):3251-3264