Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib

• Teemu P Miettinen ^[4] ; Julien Peltier ^[1] ; Anetta Härtlova ^[1] ; Marek Gierliński ^[2] ; Valerie M Jansen ^[3] ; Matthias Trost ^[1] ; Mikael Björklund ^[2]
  1. [1] MRC Protein Phosphorylation and Ubiquitylation Unit

     MRC Protein Phosphorylation and Ubiquitylation Unit

     Reino Unido

     
  2. [2] University of Dundee

     University of Dundee

     Reino Unido

     
  3. [3] Vanderbilt University Medical Center

     Vanderbilt University Medical Center

     Estados Unidos

     
  4. [4] 1 Division of Cell and Developmental Biology University of Dundee Dundee UK; 2 MRC Protein Phosphorylation and Ubiquitylation Unit University of Dundee Dundee UK; 3 MRC Laboratory for Molecular Cell Biology University College London London UK; 4 Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 10, 2018, págs. 3-3
• Idioma: inglés
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  • Palbociclib is a CDK4/6 inhibitor approved for metastatic estrogen receptor‐positive breast cancer. In addition to G1 cell cycle arrest, palbociclib treatment results in cell senescence, a phenotype that is not readily explained by CDK4/6 inhibition. In order to identify a molecular mechanism responsible for palbociclib‐induced senescence, we performed thermal proteome profiling of MCF7 breast cancer cells. In addition to affecting known CDK4/6 targets, palbociclib induces a thermal stabilization of the 20S proteasome, despite not directly binding to it. We further show that palbociclib treatment increases proteasome activity independently of the ubiquitin pathway. This leads to cellular senescence, which can be counteracted by proteasome inhibitors. Palbociclib‐induced proteasome activation and senescence is mediated by reduced proteasomal association of ECM29. Loss of ECM29 activates the proteasome, blocks cell proliferation, and induces a senescence‐like phenotype. Finally, we find that ECM29 mRNA levels are predictive of relapse‐free survival in breast cancer patients treated with endocrine therapy. In conclusion, thermal proteome profiling identifies the proteasome and ECM29 protein as mediators of palbociclib activity in breast cancer cells.