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

Huai Qiang Ju, Haoqiang Ying, Tian Tian, Jianhua Ling, Jie Fu, Yu Lu, Min Wu, Lifeng Yang, Abhinav Achreja, Gang Chen, Zhuonan Zhuang, Huamin Wang, Deepak Nagrath, Jun Yao, Mien Chie Hung, Ronald A. DePinho, Peng Huang, Rui Hua Xu, Paul J. Chiao

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 p22 phox, 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.

Original languageEnglish (US)
Article number14437
JournalNature communications
Volume8
DOIs
StatePublished - Feb 24 2017

Fingerprint

Adenocarcinoma
Chemical activation
activation
NAD
deactivation
glycolysis
Oxidation
oxidation
NADPH Oxidase
gene expression
oxidase
Cell growth
cultured cells
Gene expression
enzymes
Gene Expression Profiling
Glycolysis
Cells
Catalytic Domain
Metabolic Activation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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

In: Nature communications, Vol. 8, 14437, 24.02.2017.

Research output: Contribution to journalArticle

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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 p22 phox, 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.",
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AU - Ju, Huai Qiang

AU - Ying, Haoqiang

AU - Tian, Tian

AU - Ling, Jianhua

AU - Fu, Jie

AU - Lu, Yu

AU - Wu, Min

AU - Yang, Lifeng

AU - Achreja, Abhinav

AU - Chen, Gang

AU - Zhuang, Zhuonan

AU - Wang, Huamin

AU - Nagrath, Deepak

AU - Yao, Jun

AU - Hung, Mien Chie

AU - DePinho, Ronald A.

AU - Huang, Peng

AU - Xu, Rui Hua

AU - Chiao, Paul J.

PY - 2017/2/24

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