p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.
p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.
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DOI：
10.1158/0008-5472.can-19-3281
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发表时间：
2020-08-15
期刊：
影响因子：
11.2
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中科院分区：
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KRAS在大多数胰腺导管腺癌（PDAC）中发生突变，但仍然无法药物治疗。在这里，我们报道p38gamma MAPK是一个新的治疗靶点，它通过连接KRAS信号和有氧糖酵解（也称为Warburg效应）来促进PDAC的肿瘤发生。p38 γ与依赖突变KRAS的糖酵解激活剂PFKFB3相互作用。KRAS转化和p38 γ的过表达增加了PFKFB3和葡萄糖转运蛋白GLUT2的表达；相反，沉默突变体KRAS和p38 γ降低了PFKFB3和GLUT2的表达。p38 γ在S467位点磷酸化PFKFB3，稳定PFKFB3，促进它们与GLUT2的相互作用。胰腺敲除（KO） p38 γ降低了KPC小鼠的p-PFKFB3/PFKFB3/GLUT2蛋白水平，减少了有氧糖酵解，并抑制了PDAC的肿瘤发生。PFKFB3和GLUT2依赖于p38 γ刺激糖酵解和PDAC生长，而p38 γ需要PFKFB3/S467来促进这些活性。p38 γ抑制剂与PFKFB3抑制剂共同抑制依赖于p38 γ的有氧糖酵解和PDAC生长。此外，p38 γ、p-PFKFB3、PFKFB3和GLUT2在PDAC中的过表达预示着不良的临床预后。这些结果表明，p38gamma通过PFKFB3和GLUT2连接KRAS癌基因信号和有氧糖酵解，促进胰腺肿瘤发生，p38gamma和PFKFB3可能是PDAC治疗干预的靶点。
KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here we report that p38gamma MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38gamma interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38gamma increased expression of PFKFB3 and glucose transporter GLUT2; conversely, silencing mutant KRAS and p38gamma decreased PFKFB3 and GLUT2 expression. p38gamma phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout (KO) of p38gamma decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38gamma to stimulate glycolysis and PDAC growth and p38gamma required PFKFB3/S467 to promote these activities. A p38gamma inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38gamma. Moreover, overexpression of p38gamma, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38gamma links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38gamma and PFKFB3 may be targeted for therapeutic intervention in PDAC.