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Targeting the mTOR signaling pathway to inhibit lung cell senescence in COPD

Amal Houssaini, Kanny Kebe, Marielle Breau, Elisabeth Marcos, Shariq Abid, Dominique Rideau, Jin Huang, Aya Attwe, Emilie Bizard, Pierre Validire, Bernard Maitre, Valerie Amsellem, Silke Meiners, Serge Adnot
European Respiratory Journal 2016 48: PA4024; DOI: 10.1183/13993003.congress-2016.PA4024
Amal Houssaini
1Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Institut für Lungenbiologie, Comprehensive Pneumology Center, München, Germany
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Kanny Kebe
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Marielle Breau
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Elisabeth Marcos
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Shariq Abid
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Dominique Rideau
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Jin Huang
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Aya Attwe
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Emilie Bizard
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Pierre Validire
3Institut Mutualiste Montsouris, AP-HP, Paris, France
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Bernard Maitre
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Valerie Amsellem
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Silke Meiners
1Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Institut für Lungenbiologie, Comprehensive Pneumology Center, München, Germany
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Serge Adnot
2INSERM Unit 955, IMRB Institute, Team 8, University of Paris-Est, Creteil, Creteil, France
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Abstract

Cell senescence, defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes, might play a causal role in COPD. We previously reported that senescent cells are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. Here, we investigated whether lung cell senescence in COPD was related to overactivation of the mTOR (mechanistic target of rapamycin) signaling pathway and whether targeting this pathway inhibited cell senescence and/or suppressed the SASP in COPD. Strong activation of the mTOR-Akt signaling pathway was found in lungs from patients with COPD compared to controls, with a marked PTEN decrease and activation of mTOR complex 1 (mTORC1) substrates, and of mTORC2 substrates, together with an increase in p21 and p16 protein levels. Similar activation of the mTORC1 and mTORC2 substrates were found in cultured PA-SMCs and P-ECs from patients with COPD compared to controls. Cultured P-ECs or PA-SMCs from patients with COPD exhibited an early onset of cell senescence as assessed by a decrease in the number of population doubling (PDLs).Treatment of the cells from patients with COPD with rapamycin (10 nM) normalized the number of PDLs to that seen in controls and decreased the number of beta-gal-positive cells. Cultured PA-SMCs from SM22-TSC1-/- mice, which exhibited strong mTORC1 activation in PA-SMCs, were characterized by an early onset of cell senescence compared to control mice.These results show that the increased propensity of lung cells to senescence in COPD is related to overactivation of the mTOR signaling pathway and can be suppressed by low doses of rapamycin.

  • COPD - mechanism
  • Proteomics
  • Cell biology
  • Copyright ©the authors 2016
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Targeting the mTOR signaling pathway to inhibit lung cell senescence in COPD
Amal Houssaini, Kanny Kebe, Marielle Breau, Elisabeth Marcos, Shariq Abid, Dominique Rideau, Jin Huang, Aya Attwe, Emilie Bizard, Pierre Validire, Bernard Maitre, Valerie Amsellem, Silke Meiners, Serge Adnot
European Respiratory Journal Sep 2016, 48 (suppl 60) PA4024; DOI: 10.1183/13993003.congress-2016.PA4024

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Targeting the mTOR signaling pathway to inhibit lung cell senescence in COPD
Amal Houssaini, Kanny Kebe, Marielle Breau, Elisabeth Marcos, Shariq Abid, Dominique Rideau, Jin Huang, Aya Attwe, Emilie Bizard, Pierre Validire, Bernard Maitre, Valerie Amsellem, Silke Meiners, Serge Adnot
European Respiratory Journal Sep 2016, 48 (suppl 60) PA4024; DOI: 10.1183/13993003.congress-2016.PA4024
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