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

Details

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State: Public
Version: Final published version
Serval ID
serval:BIB_1FC6B49B76D3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence.
Journal
Nature communications
Author(s)
Revandkar A., Perciato M.L., Toso A., Alajati A., Chen J., Gerber H., Dimitrov M., Rinaldi A., Delaleu N., Pasquini E., D'Antuono R., Pinton S., Losa M., Gnetti L., Arribas A., Fraering P., Bertoni F., Nepveu A., Alimonti A.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
12/12/2016
Peer-reviewed
Oui
Volume
7
Pages
13719
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
Keywords
ADAM17 Protein/genetics, ADAM17 Protein/metabolism, Amyloid Precursor Protein Secretases/antagonists & inhibitors, Animals, Cell Line, Tumor, Cellular Senescence/drug effects, Cyclin-Dependent Kinase Inhibitor p27/metabolism, Cyclin-Dependent Kinase Inhibitor p27/physiology, Humans, Male, Mice, PTEN Phosphohydrolase/genetics, PTEN Phosphohydrolase/metabolism, Prostatic Neoplasms/drug therapy, Prostatic Neoplasms/pathology, Receptors, Notch/antagonists & inhibitors, Receptors, Notch/metabolism, Signal Transduction/drug effects, Tetrahydronaphthalenes/therapeutic use, Up-Regulation, Valine/analogs & derivatives, Valine/therapeutic use
Pubmed
Web of science
Open Access
Yes
Create date
22/12/2016 12:19
Last modification date
20/08/2019 13:55
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