Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wang, D; Bi, Y; Hu, L; Luo, Y; Ji, J; Mao, AZ; Logsdon, CD; Li, E; Abbruzzese, JL; Li, Z; Yang, VW; Lu, W

Published Date

  • February 28, 2019

Published In

Volume / Issue

  • 17 / 1

Start / End Page

  • 19 -

PubMed ID

  • 30819189

Pubmed Central ID

  • 30819189

Electronic International Standard Serial Number (EISSN)

  • 1478-811X

Digital Object Identifier (DOI)

  • 10.1186/s12964-019-0333-7

Language

  • eng

Conference Location

  • England