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 p38g MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38g interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38g increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38g decreased PFKFB3 and GLUT2 expression. p38g phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38g decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38g to stimulate glycolysis and PDAC growth and p38g required PFKFB3/S467 to promote these activities. A p38g inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38g. Moreover, overexpression of p38g, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38g links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38g and PFKFB3 may be targeted for therapeutic intervention in PDAC.Significance: These findings show that p38g links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38g and PFKFB3.

Probiotic Aspergillus oryzae produces anti-tumor mediator and exerts anti-tumor effects in pancreatic cancer through the p38 MAPK signaling pathway

“…Recently, Liberti et al revealed that heptelidic acid exerted anti-tumor effects in cells that depended on the Warburg effect (WE) 30 . Likewise, p38 MAPK signaling is known to be a key regulatory signaling pathway of glycolysis 31 – 33 in pancreatic cancer cells and our findings showed that heptelidic acid exerted an anti-tumor effect which was mediated by p38 signal transduction. These findings suggest that anticancer therapy, especially pancreatic cancer treatment, utilizing heptelidic acid may prove effective.…”

Seven Glycolysis-Related Genes Predict the Prognosis of Patients With Pancreatic Cancer

“…Moreover, most of the previous studies focused on the role of a certain gene in PDAC, and most of them studied the effect of genes on the function of PDAC cells, for example: Yang et al (2020) found that chlorogenic acid can inhibit cell bioenergy by regulating the c-Myc-TFR1 axis, thereby inhibiting pancreatic cancer. The study by Wang et al (2020) shows that p38γ links KRAS oncogene signal transduction and Warburg effect through PFBBF3 and Glut2 to promote the occurrence of pancreatic cancer. But our study creatively studied the relationship between glycolysis-related genes (GRGs) and the clinical risk of PDAC patients, and the constructed model can predict the prognosis of PDAC patients well.…”

Development and validation of glycolysis‐related prognostic score for prediction of prognosis and chemosensitivity of pancreatic ductal adenocarcinoma

“…Aerobic glycolysis is essential for cancer cells growth and invasion 22‐24 . In PDAC, recent studies reported that aerobic glycolysis of metabolic reprogramming promoted pancreatic tumorigenesis, proliferation and metastasis 8,25‐27 . Although there are many studies on the relationship between PDAC and glycolysis, researches which involve biomarkers and prognosis of patients with PDAC relating to glycolysis are seldomly reported.…”

“…A high rate of aerobic glycolysis, known as the Warburg effect, is a hallmark of cancer cell glucose metabolism 7 . Recent studies reported that aerobic glycolysis is active in PDAC in promoting pancreatic tumorigenesis, proliferation and invasion 8‐10 . Furthermore, pyruvate kinase M2, which promotes cell survival and invasion under metabolic stress by enhancing the Warburg effect in PDAC, 11 promotes PDAC invasion and metastasis through phosphorylation and stabilization of PAK2 protein 12 .…”