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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 p22phox was induced by KrasG12V-activated NF-?B. 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.

SUBMITTER: Ju HQ

PROVIDER: S-EPMC5333128 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Ju Huai-Qiang HQ Ying Haoqiang H Tian Tian T Ling Jianhua J Fu Jie J Lu Yu Y Wu Min M Yang Lifeng L Achreja Abhinav A Chen Gang G Zhuang Zhuonan Z Wang Huamin H Nagrath Deepak D Yao Jun J Hung Mien-Chie MC DePinho Ronald A RA Huang Peng P Xu Rui-Hua RH Chiao Paul J PJ

Nature communications 20170224

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<sup>phox</sup>, which is upregulated following Kras activation. Both a ...[more]

PMID: 28232723

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Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among all solid tumors. Tumorigenesis is promoted by the oncogene KRAS, and KRAS mutations are prevalent in patients with PDAC. Therefore, a comprehensive understanding of the interactions between KRAS mutations and PDAC may expediate the development of therapeutic strategies for reversing the progression of malignant tumors. Our study aims at establishing and validating a prediction model of KRAS mutations in patients with PDAC based on survival analysis and mRNA expression.MethodsA total of 184 and 412 patients with PDAC from The Cancer Genome Atlas (TCGA) database and the International Cancer Genome Consortium (ICGC), respectively, were included in the study.ResultsAfter tumor mutation profile and copy number variation (CNV) analyses, we established and validated a prediction model of KRAS mutations, based on survival analysis and mRNA expression, that contained seven genes: CSTF2, FAF2, KIF20B, AKR1A1, APOM, KRT6C, and CD70. We confirmed that the model has a good predictive ability for the prognosis of overall survival (OS) in patients with KRAS-mutated PDAC. Then, we analyzed differential biological pathways, especially the ferroptosis pathway, through principal component analysis, pathway enrichment analysis, Gene Ontology (GO) enrichment analysis, and gene set enrichment analysis (GSEA), with which patients were classified into low- or high-risk groups. Pathway enrichment results revealed enrichment in the cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450, and viral protein interaction with cytokine and cytokine receptor pathways. Most of the enriched pathways are metabolic pathways predominantly enriched by downregulated genes, suggesting numerous downregulated metabolic pathways in the high-risk group. Subsequent tumor immune infiltration analysis indicated that neutrophil infiltration, resting CD4 memory T cells, and resting natural killer (NK) cells correlated with the risk score. After verifying that the seven gene expression levels in different KRAS-mutated pancreatic cancer cell lines were similar to that in the model, we screened potential drugs related to the risk score.DiscussionThis study established, analyzed, and validated a model for predicting the prognosis of PDAC based on risk stratification according to KRAS mutations, and identified differential pathways and highly effective drugs.

Dataset Information

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

Publications

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

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