Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma

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dc.citation.articleNumber14437
dc.citation.journalTitleNature Communicationsen_US
dc.contributor.authorJu, Huai-Qiangen_US
dc.contributor.authorYing, Haoqiangen_US
dc.contributor.authorTian, Tianen_US
dc.contributor.authorLing, Jianhuaen_US
dc.contributor.authorFu, Jieen_US
dc.contributor.authorLu, Yuen_US
dc.contributor.authorWu, Minen_US
dc.contributor.authorYang, Lifengen_US
dc.contributor.authorAchreja, Abhinaven_US
dc.contributor.authorChen, Gangen_US
dc.contributor.authorZhuang, Zhuonanen_US
dc.contributor.authorWang, Huaminen_US
dc.contributor.authorNagrath, Deepaken_US
dc.contributor.authorYao, Junen_US
dc.contributor.authorHung, Mien-Chieen_US
dc.contributor.authorDePinho, Ronald A.en_US
dc.contributor.authorHuang, Pengen_US
dc.contributor.authorXu, Rui-Huaen_US
dc.contributor.authorChiao, Paul J.en_US
dc.contributor.orgLaboratory for Systems Biology of Human Diseasesen_US
dc.date.accessioned2017-03-07T18:24:16Z
dc.date.available2017-03-07T18:24:16Z
dc.date.issued2017en_US
dc.description.abstractKras 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.en_US
dc.identifier.citationJu, Huai-Qiang, Ying, Haoqiang, Tian, Tian, et al.. "Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma." <i>Nature Communications,</i> (2017) Springer Nature: http://dx.doi.org/10.1038/ncomms14437.
dc.identifier.doihttp://dx.doi.org/10.1038/ncomms14437en_US
dc.identifier.urihttps://hdl.handle.net/1911/94029
dc.language.isoengen_US
dc.publisherSpringer Nature
dc.rightsThis 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleMutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinomaen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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