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

Détails

Ressource 1Télécharger: ncomms13719.pdf (1988.49 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_1FC6B49B76D3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence.
Périodique
Nature communications
Auteur⸱e⸱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
Statut éditorial
Publié
Date de publication
12/12/2016
Peer-reviewed
Oui
Volume
7
Pages
13719
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
22/12/2016 11:19
Dernière modification de la notice
21/11/2022 8:30
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