Critical role for arginase 2 in obesity-associated pancreatic cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-08-14

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

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. More... »

PAGES

242

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-017-00331-y

DOI

http://dx.doi.org/10.1038/s41467-017-00331-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1091206341

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28808255


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32 schema: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 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.
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39 Arg1
40 accumulation
41 adenocarcinoma
42 alterations
43 ammonia accumulation
44 analysis
45 arginase
46 arginase-2
47 arginine
48 arginine catabolism
49 body mass index
50 cancer
51 catabolism
52 critical role
53 cycle
54 dependency
55 ductal adenocarcinoma
56 enrichment
57 exhibit
58 factors
59 flux
60 form
61 growth
62 identification
63 index
64 infusion
65 lethal malignancy
66 levels
67 loss
68 malignancy
69 mass index
70 metabolic alterations
71 metabolic dependencies
72 metabolism
73 mitochondrial form
74 model
75 mouse model
76 nitrogen flux
77 nitrogen metabolism
78 obese mouse model
79 obesity
80 ornithine
81 pancreatic cancer
82 pancreatic ductal adenocarcinoma
83 pathway
84 patient tumors
85 recent identification
86 repository
87 risk factors
88 role
89 show
90 shunting
91 significant ammonia accumulation
92 specific dependencies
93 therapeutic window
94 transcriptional enrichment
95 tumors
96 urea cycle
97 vivo infusion
98 window
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