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

doi:10.1038/ncomms14437

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

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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 p22^phox was induced by Kras^G12V -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 language	English (US)
Article number	14437
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14437
State	Published - Feb 24 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Ju, H. Q., Ying, H., Tian, T., Ling, J., Fu, J., Lu, Y., Wu, M., Yang, L., Achreja, A., Chen, G., Zhuang, Z., Wang, H., Nagrath, D., Yao, J., Hung, M. C., DePinho, R. A., Huang, P., Xu, R. H., & Chiao, P. J. (2017). Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma. Nature communications, 8, Article 14437. https://doi.org/10.1038/ncomms14437

Ju, HQ, Ying, H, Tian, T, Ling, J, Fu, J, Lu, Y, Wu, M, Yang, L, Achreja, A, Chen, G, Zhuang, Z, Wang, H, Nagrath, D, Yao, J, Hung, MC, DePinho, RA, Huang, P, Xu, RH & Chiao, PJ 2017, 'Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma', Nature communications, vol. 8, 14437. https://doi.org/10.1038/ncomms14437

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

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.",

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

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doi = "10.1038/ncomms14437",

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T1 - Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma

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

Y1 - 2017/2/24

N2 - 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.

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

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MD Anderson CCSG core facilities

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