p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis
Open Access
- 23 June 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (16), 3251-3264
- https://doi.org/10.1158/0008-5472.CAN-19-3281
Abstract
KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here, we report that p38 gamma MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38 gamma interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38 gamma increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38 gamma decreased PFKFB3 and GLUT2 expression. p38 gamma phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38 gamma decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38 gamma to stimulate glycolysis and PDAC growth and p38 gamma required PFKFB3/S467 to promote these activities. A p38 gamma inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38 gamma. Moreover, overexpression of p38 gamma, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38 gamma links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38 gamma and PFKFB3 may be targeted for therapeutic intervention in PDAC. Significance: These findings show that p38 gamma links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38 gamma and PFKFB3.Other Versions
Funding Information
- Department of Veterans Affairs (1I01BX002883)
- Department of Defense (BC141898)
- NIH (R01 CA91576)
- Cancer Center of the Medical College of Wisconsin
- Natural Scientific Foundation of China (81402503)
- Science and Technology Program of Guangzhou, China (201802020002)
- The Basic Scientific Fund of Sun Yat-Sen University (19ypy196)
- NIH (R01 CA178960, CA226279)
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