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 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 p22phoxwas 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.
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Huai-Qiang
authors.initials: HQ
authors.lastname: Ju
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Tian
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ling
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, Texas 77005, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, Texas 77005, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Achreja
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zhuonan
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, Texas 77005, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D057075:Enzyme Assays; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009249:NADP / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D009249:NADP; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C086986:CYBA protein, human; D016283:Proto-Oncogene Proteins p21(ras)