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

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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
    The University of Texas MD Anderson Cancer Center)

  • 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
    The University of Texas Graduate School of Biomedical Sciences)

  • Ronald A. DePinho

    (The University of Texas Graduate School of Biomedical Sciences
    The University of Texas MD Anderson Cancer Center)

  • Peng Huang

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
    The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences)

  • 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
    The University of Texas Graduate School of Biomedical Sciences)

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.

Suggested Citation

  • 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 Hun, 2017. "Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14437
    DOI: 10.1038/ncomms14437
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