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 () and Paul J. Chiao ()
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Huai-Qiang Ju: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Haoqiang Ying: The University of Texas MD Anderson Cancer Center
Tian Tian: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Jianhua Ling: The University of Texas MD Anderson Cancer Center
Jie Fu: The University of Texas MD Anderson Cancer Center
Yu Lu: The University of Texas MD Anderson Cancer Center
Min Wu: The University of Texas MD Anderson Cancer Center
Lifeng Yang: Laboratory for Systems Biology of Human Diseases, Rice University
Abhinav Achreja: Laboratory for Systems Biology of Human Diseases, Rice University
Gang Chen: The University of Texas MD Anderson Cancer Center
Zhuonan Zhuang: The University of Texas MD Anderson Cancer Center
Huamin Wang: The University of Texas MD Anderson Cancer Center
Deepak Nagrath: Laboratory for Systems Biology of Human Diseases, Rice University
Jun Yao: The University of Texas MD Anderson Cancer Center
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center
Ronald A. DePinho: The University of Texas Graduate School of Biomedical Sciences
Peng Huang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Rui-Hua Xu: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Paul J. Chiao: The University of Texas MD Anderson Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14437

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