Journal article

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

  • Revandkar, Ajinkya Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland
  • Perciato, Maria Luna Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Toso, Alberto Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Alajati, Abdullah Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Chen, Jingjing Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland
  • Gerber, Hermeto Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland - Foundation Eclosion, Plan-Les-Ouates CH 1228, Switzerland - Campus Biotech Innovation Park, Geneva CH 1202, Switzerland
  • Dimitrov, Mitko Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland
  • Rinaldi, Andrea Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Delaleu, Nicolas Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway
  • Pasquini, Emiliano Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • D’Antuono, Rocco Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Pinton, Sandra Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Losa, Marco Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Gnetti, Letizia Pathology Unit, University Hospital of Parma, Parma 43126, Italy
  • Arribas, Alberto Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Fraering, Patrick Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH 1015, Switzerland - Foundation Eclosion, Plan-Les-Ouates CH 1228, Switzerland - Campus Biotech Innovation Park, Geneva CH 1202, Switzerland
  • Bertoni, Francesco Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Nepveu, Alain Rosalind and Morris Goodman Cancer Research Center, Department of Oncology, Biochemistry and Medicine, McGill University, Montreal, Quebec, Canada H3A1A3
  • Andrea Alimonti Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne CH 1011, Switzerland
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    12.12.2016
Published in:
  • Nature communications. - 2016, vol. 7, p. 13719
English 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.
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  • English
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Medicine
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https://susi.usi.ch/usi/documents/319005
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