IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v7y2016i1d10.1038_ncomms13719.html
   My bibliography  Save this article

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Author

Listed:
  • Ajinkya Revandkar

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
    Faculty of Biology and Medicine, University of Lausanne (UNIL))

  • Maria Luna Perciato

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Alberto Toso

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Abdullah Alajati

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Jingjing Chen

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
    Faculty of Biology and Medicine, University of Lausanne (UNIL))

  • Hermeto Gerber

    (Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
    Foundation Eclosion
    Campus Biotech Innovation Park)

  • Mitko Dimitrov

    (Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Andrea Rinaldi

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Nicolas Delaleu

    (Broegelmann Research Laboratory, University of Bergen)

  • Emiliano Pasquini

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Rocco D’Antuono

    (Institute for Research in Biomedicine, University of Italian Switzerland, Via Vincenzo Vela 6, Bellinzona 6500, Switzerland)

  • Sandra Pinton

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Marco Losa

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Letizia Gnetti

    (Pathology Unit, University Hospital of Parma)

  • Alberto Arribas

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Patrick Fraering

    (Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
    Foundation Eclosion
    Campus Biotech Innovation Park)

  • Francesco Bertoni

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI))

  • Alain Nepveu

    (Rosalind and Morris Goodman Cancer Research Center, Biochemistry and Medicine, McGill University)

  • Andrea Alimonti

    (Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI)
    Faculty of Biology and Medicine, University of Lausanne (UNIL))

Abstract

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.

Suggested Citation

  • Ajinkya Revandkar & Maria Luna Perciato & Alberto Toso & Abdullah Alajati & Jingjing Chen & Hermeto Gerber & Mitko Dimitrov & Andrea Rinaldi & Nicolas Delaleu & Emiliano Pasquini & Rocco D’Antuono & S, 2016. "Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13719
    DOI: 10.1038/ncomms13719
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms13719
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms13719?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:7:y:2016:i:1:d:10.1038_ncomms13719. 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.