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- Title
Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS.
- Authors
Wang, Dan; Bi, Yawei; Hu, Lianghao; Luo, Yongde; Ji, Juntao; Mao, Albert Z.; Logsdon, Craig D.; Li, Ellen; Abbruzzese, James L.; Li, Zhaoshen; Yang, Vincent W.; Lu, Weiqin
- Abstract
Oncogenic KRAS plays a vital role in controlling tumor metabolism by enhancing aerobic glycolysis. Obesity driven by chronic consumption of high-fat diet (HFD) is a major risk factor for oncogenic KRAS-mediated pancreatic ductal adenocarcinoma (PDAC). However, the role of HFD in KRAS-mediated metabolic reprogramming has been obscure. Here, by using genetically engineered mouse models expressing an endogenous level of KRASG12D in pancreatic acinar cells, we demonstrate that hyperactivation of KRASG12D by obesogenic HFD, as compared to carbohydrate-rich diet, is responsible for enhanced aerobic glycolysis that associates with critical pathogenic responses in the path towards PDAC. Ablation of Cox-2 attenuates KRAS hyperactivation leading to the reversal of both aggravated aerobic glycolysis and high-grade dysplasia under HFD challenge. Our data highlight a pivotal role of the cooperative interaction between obesity-ensuing HFD and oncogenic KRAS in driving the heightened aerobic glycolysis during pancreatic tumorigenesis and suggest that in addition to directly targeting KRAS and aerobic glycolysis pathway, strategies to target the upstream of KRAS hyperactivation may bear important therapeutic value.
- Subjects
HIGH-fat diet; GLYCOLYSIS; PANCREATIC duct; ADENOCARCINOMA; PANCREATIC acinar cells; OBESITY
- Publication
Cell Communication & Signaling, 2019, Vol 17, Issue 1, pN.PAG
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-019-0333-7