Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis. Cancer Res 2020 08 15;80(16):3251-3264

Date

06/26/2020

Pubmed ID

32580961

DOI

10.1158/0008-5472.CAN-19-3281

Scopus ID

2-s2.0-85089787021   7 Citations

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. 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.

Author List

Wang F, Qi XM, Wertz R, Mortensen M, Hagen C, Evans J, Sheinin Y, James M, Liu P, Tsai S, Thomas J, Mackinnon A, Dwinell M, Myers CR, Bartrons Bach R, Fu L, Chen G

Authors

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Xiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Yuri M. Sheinin MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin
James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin
Susan Tsai MD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aerobiosis
Animals
Carcinoma, Pancreatic Ductal
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Collagen
Drug Combinations
Female
Gene Knockout Techniques
Gene Silencing
Genes, ras
Genotyping Techniques
Glucose Transporter Type 2
Glycolysis
Humans
Laminin
Male
Mice
Mitogen-Activated Protein Kinase 12
Neoplasm Proteins
Pancreatic Neoplasms
Phosphofructokinase-2
Phosphorylation
Prognosis
Proteoglycans
Proto-Oncogene Proteins p21(ras)