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COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells.
McHugh, Domhnall; Sun, Bin; Gutierrez-Muñoz, Carmen; Hernández-González, Fernanda; Mellone, Massimiliano; Guiho, Romain; Duran, Imanol; Pombo, Joaquim; Pietrocola, Federico; Birch, Jodie; Kallemeijn, Wouter W; Khadayate, Sanjay; Dharmalingam, Gopuraja; Vernia, Santiago; Tate, Edward W; Martínez-Barbera, Juan Pedro; Withers, Dominic J; Thomas, Gareth J; Serrano, Manuel; Gil, Jesús.
Afiliação
  • McHugh D; MRC Laboratory of Medical Sciences (LMS), London, UK.
  • Sun B; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
  • Gutierrez-Muñoz C; MRC Laboratory of Medical Sciences (LMS), London, UK.
  • Hernández-González F; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
  • Mellone M; MRC Laboratory of Medical Sciences (LMS), London, UK.
  • Guiho R; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
  • Duran I; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • Pombo J; Department of Pulmonology, ICR, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
  • Pietrocola F; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Birch J; School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
  • Kallemeijn WW; AstraZeneca, Immuno-Oncology Discovery, Oncology R&D, Cambridge, UK.
  • Khadayate S; Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK.
  • Dharmalingam G; MRC Laboratory of Medical Sciences (LMS), London, UK.
  • Vernia S; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
  • Tate EW; MRC Laboratory of Medical Sciences (LMS), London, UK.
  • Martínez-Barbera JP; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
  • Withers DJ; Karolinska Institute, Department of Biosciences and Nutrition, Huddinge, Sweden.
  • Thomas GJ; MRC Laboratory of Medical Sciences (LMS), London, UK.
  • Serrano M; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
  • Gil J; Department of Chemistry, Molecular Sciences Research Hub, London, UK.
Nat Cell Biol ; 25(12): 1804-1820, 2023 Dec.
Article em En | MEDLINE | ID: mdl-38012402
Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Senoterapia / Neoplasias Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Senoterapia / Neoplasias Idioma: En Ano de publicação: 2023 Tipo de documento: Article