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Critical role for arginase 2 in obesity-associated pancreatic cancer
Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth an...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556090/ https://www.ncbi.nlm.nih.gov/pubmed/28808255 http://dx.doi.org/10.1038/s41467-017-00331-y |
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author | Zaytouni, Tamara Tsai, Pei-Yun Hitchcock, Daniel S. DuBois, Cory D. Freinkman, Elizaveta Lin, Lin Morales-Oyarvide, Vicente Lenehan, Patrick J. Wolpin, Brian M. Mino-Kenudson, Mari Torres, Eduardo M. Stylopoulos, Nicholas Clish, Clary B. Kalaany, Nada Y. |
author_facet | Zaytouni, Tamara Tsai, Pei-Yun Hitchcock, Daniel S. DuBois, Cory D. Freinkman, Elizaveta Lin, Lin Morales-Oyarvide, Vicente Lenehan, Patrick J. Wolpin, Brian M. Mino-Kenudson, Mari Torres, Eduardo M. Stylopoulos, Nicholas Clish, Clary B. Kalaany, Nada Y. |
author_sort | Zaytouni, Tamara |
collection | PubMed |
description | Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of (15)N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of (15)N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer. |
format | Online Article Text |
id | pubmed-5556090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55560902017-08-17 Critical role for arginase 2 in obesity-associated pancreatic cancer Zaytouni, Tamara Tsai, Pei-Yun Hitchcock, Daniel S. DuBois, Cory D. Freinkman, Elizaveta Lin, Lin Morales-Oyarvide, Vicente Lenehan, Patrick J. Wolpin, Brian M. Mino-Kenudson, Mari Torres, Eduardo M. Stylopoulos, Nicholas Clish, Clary B. Kalaany, Nada Y. Nat Commun Article Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of (15)N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of (15)N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer. Nature Publishing Group UK 2017-08-14 /pmc/articles/PMC5556090/ /pubmed/28808255 http://dx.doi.org/10.1038/s41467-017-00331-y Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zaytouni, Tamara Tsai, Pei-Yun Hitchcock, Daniel S. DuBois, Cory D. Freinkman, Elizaveta Lin, Lin Morales-Oyarvide, Vicente Lenehan, Patrick J. Wolpin, Brian M. Mino-Kenudson, Mari Torres, Eduardo M. Stylopoulos, Nicholas Clish, Clary B. Kalaany, Nada Y. Critical role for arginase 2 in obesity-associated pancreatic cancer |
title | Critical role for arginase 2 in obesity-associated pancreatic cancer |
title_full | Critical role for arginase 2 in obesity-associated pancreatic cancer |
title_fullStr | Critical role for arginase 2 in obesity-associated pancreatic cancer |
title_full_unstemmed | Critical role for arginase 2 in obesity-associated pancreatic cancer |
title_short | Critical role for arginase 2 in obesity-associated pancreatic cancer |
title_sort | critical role for arginase 2 in obesity-associated pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556090/ https://www.ncbi.nlm.nih.gov/pubmed/28808255 http://dx.doi.org/10.1038/s41467-017-00331-y |
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