IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_s41467-017-00331-y.html
   My bibliography  Save this article

Critical role for arginase 2 in obesity-associated pancreatic cancer

Author

Listed:
  • Tamara Zaytouni

    (Boston Children’s Hospital
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Pei-Yun Tsai

    (Boston Children’s Hospital
    Harvard Medical School)

  • Daniel S. Hitchcock

    (Broad Institute of Harvard and MIT)

  • Cory D. DuBois

    (Boston Children’s Hospital
    Broad Institute of Harvard and MIT)

  • Elizaveta Freinkman

    (Whitehead Institute for Biomedical Research
    Research Triangle Park)

  • Lin Lin

    (Harvard Medical School)

  • Vicente Morales-Oyarvide

    (Harvard Medical School)

  • Patrick J. Lenehan

    (Boston Children’s Hospital
    Harvard Medical School)

  • Brian M. Wolpin

    (Harvard Medical School)

  • Mari Mino-Kenudson

    (Massachusetts General Hospital and Harvard Medical School)

  • Eduardo M. Torres

    (University of Massachusetts Medical School)

  • Nicholas Stylopoulos

    (Boston Children’s Hospital
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Clary B. Clish

    (Broad Institute of Harvard and MIT)

  • Nada Y. Kalaany

    (Boston Children’s Hospital
    Harvard Medical School
    Broad Institute of Harvard and MIT)

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.

Suggested Citation

  • 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, 2017. "Critical role for arginase 2 in obesity-associated pancreatic cancer," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00331-y
    DOI: 10.1038/s41467-017-00331-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-017-00331-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-017-00331-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00331-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.