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dc.contributor.authorJu, Huai-Qiang
Ying, Haoqiang
Tian, Tian
Ling, Jianhua
Fu, Jie
Lu, Yu
Wu, Min
Yang, Lifeng
Achreja, Abhinav
Chen, Gang
Zhuang, Zhuonan
Wang, Huamin
Nagrath, Deepak
Yao, Jun
Hung, Mien-Chie
DePinho, Ronald A.
Huang, Peng
Xu, Rui-Hua
Chiao, Paul J.
dc.date.accessioned 2017-03-07T18:24:16Z
dc.date.available 2017-03-07T18:24:16Z
dc.date.issued 2017
dc.identifier.citation Ju, Huai-Qiang, Ying, Haoqiang, Tian, Tian, et al.. "Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma." Nature Communications, (2017) Springer Nature: http://dx.doi.org/10.1038/ncomms14437.
dc.identifier.urihttps://hdl.handle.net/1911/94029
dc.description.abstract Kras activation and p16 inactivation are required to develop pancreatic ductal adenocarcinoma (PDAC). However, the biochemical mechanisms underlying these double alterations remain unclear. Here we discover that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyse the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 requires catalytic subunit p22phox, which is upregulated following Kras activation. Both alterations are also detectable in PDAC cell lines and patient specimens. Furthermore, we show that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC cell growth. Mechanistically, NOX4 was induced through p16-Rb-regulated E2F and p22phox was induced by KrasG12V-activated NF-κB. In conclusion, we provide a biochemical explanation for the cooperation between p16 inactivation and Kras activation in PDAC development and suggest that NOX4 is a potential therapeutic target for PDAC.
dc.language.iso eng
dc.publisher Springer Nature
dc.rights This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.title Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma
dc.type Journal article
dc.citation.journalTitle Nature Communications
dc.contributor.org Laboratory for Systems Biology of Human Diseases
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1038/ncomms14437
dc.identifier.pmid 28232723
dc.type.publication publisher version
dc.citation.articleNumber 14437


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