Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS
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-mediat...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2019-02-01
|
Series: | Cell Communication and Signaling |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s12964-019-0333-7 |
id |
doaj-ae0f83ad196b454d86c5e4a13795292a |
---|---|
record_format |
Article |
spelling |
doaj-ae0f83ad196b454d86c5e4a13795292a2020-11-25T01:27:49ZengBMCCell Communication and Signaling1478-811X2019-02-011711910.1186/s12964-019-0333-7Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRASDan Wang0Yawei Bi1Lianghao Hu2Yongde Luo3Juntao Ji4Albert Z. Mao5Craig D. Logsdon6Ellen Li7James L. Abbruzzese8Zhaoshen Li9Vincent W. Yang10Weiqin Lu11Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookDivision of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookDepartment of Gastroenterology, Changhai HospitalSchool of Pharmaceutical Science, Wenzhou Medical UniversityDivision of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookDivision of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookDepartment of Cancer Biology, University of Texas MD Anderson Cancer CenterDivision of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookDivision of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke UniversityDepartment of Gastroenterology, Changhai HospitalDivision of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookDivision of Gastroenterology and Hepatology, Department of Medicine, Stony Brook of University School of Medicine, Stony BrookAbstract 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.http://link.springer.com/article/10.1186/s12964-019-0333-7KRASPancreatic cancerGlycolysisHigh-fat dietObesityCOX-2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dan Wang Yawei Bi Lianghao Hu Yongde Luo Juntao Ji Albert Z. Mao Craig D. Logsdon Ellen Li James L. Abbruzzese Zhaoshen Li Vincent W. Yang Weiqin Lu |
spellingShingle |
Dan Wang Yawei Bi Lianghao Hu Yongde Luo Juntao Ji Albert Z. Mao Craig D. Logsdon Ellen Li James L. Abbruzzese Zhaoshen Li Vincent W. Yang Weiqin Lu Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS Cell Communication and Signaling KRAS Pancreatic cancer Glycolysis High-fat diet Obesity COX-2 |
author_facet |
Dan Wang Yawei Bi Lianghao Hu Yongde Luo Juntao Ji Albert Z. Mao Craig D. Logsdon Ellen Li James L. Abbruzzese Zhaoshen Li Vincent W. Yang Weiqin Lu |
author_sort |
Dan Wang |
title |
Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS |
title_short |
Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS |
title_full |
Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS |
title_fullStr |
Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS |
title_full_unstemmed |
Obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic KRAS |
title_sort |
obesogenic high-fat diet heightens aerobic glycolysis through hyperactivation of oncogenic kras |
publisher |
BMC |
series |
Cell Communication and Signaling |
issn |
1478-811X |
publishDate |
2019-02-01 |
description |
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. |
topic |
KRAS Pancreatic cancer Glycolysis High-fat diet Obesity COX-2 |
url |
http://link.springer.com/article/10.1186/s12964-019-0333-7 |
work_keys_str_mv |
AT danwang obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT yaweibi obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT lianghaohu obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT yongdeluo obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT juntaoji obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT albertzmao obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT craigdlogsdon obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT ellenli obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT jameslabbruzzese obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT zhaoshenli obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT vincentwyang obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras AT weiqinlu obesogenichighfatdietheightensaerobicglycolysisthroughhyperactivationofoncogenickras |
_version_ |
1725103059436044288 |