Critical role for arginase 2 in obesity-associated pancreatic cancer.

Abstract

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 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-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.Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.

• Authors: Tamara Zaytouni, Pei-Yun Tsai, Daniel S Hitchcock, Cory D DuBois, Elizaveta Freinkman, Lin Lin, Vicente Morales-Oyarvide, Patrick J Lenehan, Brian M Wolpin, Mari Mino-Kenudson, Eduardo M Torres, Nicholas Stylopoulos, Clary B Clish, Nada Y Kalaany
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 242 (08 14 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28808255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AGR2 protein, human
• Agr2 protein, mouse
• Mucoproteins
• Oncogene Proteins
• Proteins
• Arginine
• Ornithine

Topics

• Animals
• Arginine (metabolism)
• Carcinoma, Pancreatic Ductal (enzymology, etiology, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Knockout
• Mitochondria (enzymology, metabolism)
• Mucoproteins (genetics, metabolism)
• Obesity (complications)
• Oncogene Proteins
• Ornithine (metabolism)
• Pancreatic Neoplasms (enzymology, etiology, genetics, metabolism)
• Proteins (genetics, metabolism)