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Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence
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Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence
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Journal Article
Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence
2016
Overview
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.
Notch signalling is involved in prostate cancer progression and therapeutic resistance. Here, the authors show that loss of PTEN in prostate cancer models results in increased Notch1 cleavage and activation through CUX1-mediated transactivation of ADAM17.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ Amyloid Precursor Protein Secretases - antagonists & inhibitors
/ Animals
/ Cellular Senescence - drug effects
/ Cyclin-Dependent Kinase Inhibitor p27 - metabolism
/ Cyclin-Dependent Kinase Inhibitor p27 - physiology
/ Genes
/ Humanities and Social Sciences
/ Humans
/ Ligands
/ Male
/ Mice
/ Mutation
/ Oncology
/ Prostatic Neoplasms - drug therapy
/ Prostatic Neoplasms - pathology
/ Proteins
/ PTEN Phosphohydrolase - genetics
/ PTEN Phosphohydrolase - metabolism
/ Receptors, Notch - antagonists & inhibitors
/ Receptors, Notch - metabolism
/ Science
/ Signal Transduction - drug effects
/ Tetrahydronaphthalenes - therapeutic use
/ Tumors
