Oncotarget

Research Papers: Gerotarget (Focus on Aging):

ATF6α regulates morphological changes associated with senescence in human fibroblasts

Clémentine Druelle, Claire Drullion, Julie Deslé, Nathalie Martin, Laure Saas, Johanna Cormenier, Nicolas Malaquin, Ludovic Huot, Christian Slomianny, Fatima Bouali, Chantal Vercamer, David Hot, Albin Pourtier, Eric Chevet, Corinne Abbadie, Olivier Pluquet _

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Oncotarget. 2016; 7:67699-67715. https://doi.org/10.18632/oncotarget.11505

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Abstract

Clémentine Druelle1,6,*, Claire Drullion1,*, Julie Deslé1,*, Nathalie Martin1, Laure Saas1, Johanna Cormenier1, Nicolas Malaquin1,7, Ludovic Huot2, Christian Slomianny3, Fatima Bouali1, Chantal Vercamer1, David Hot2, Albin Pourtier1, Eric Chevet4,5, Corinne Abbadie1 and Olivier Pluquet1

1 Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France

2 Université de Lille, Institut Pasteur de Lille, INSERM, CNRS UMR8204, Centre d’Infection et d’Immunité de Lille, Lille, France

3 Université de Lille, INSERM U1003, Villeneuve d’Ascq, France

4 Oncogenesis, Stress, Signaling, INSERM ER-440 Université de Rennes, Rennes, France

5 Centre de Lutte Contre le Cancer Eugene Marquis, Rennes, France

6 Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland

7 Institut du Cancer de Montréal, Montréal, QC, Canada

* These authors have contributed equally to this work

Correspondence to:

Olivier Pluquet, email:

Keywords: senescence, unfolded protein response, ATF6α, endoplasmic reticulum, normal human dermal fibroblast, Gerotarget

Received: June 22, 2016 Accepted: August 02, 2016 Published: August 22, 2016

Abstract

Cellular senescence is known as an anti-tumor barrier and is characterized by a number of determinants including cell cycle arrest, senescence associated β-galactosidase activity and secretion of pro-inflammatory mediators. Senescent cells are also subjected to enlargement, cytoskeleton-mediated shape changes and organelle alterations. However, the underlying molecular mechanisms responsible for these last changes remain still uncharacterized. Herein, we have identified the Unfolded Protein Response (UPR) as a player controlling some morphological aspects of the senescent phenotype. We show that senescent fibroblasts exhibit ER expansion and mild UPR activation, but conserve an ER stress adaptive capacity similar to that of exponentially growing cells. By genetically invalidating the three UPR sensors in senescent fibroblasts, we demonstrated that ATF6α signaling dictates senescence-associated cell shape modifications. We also show that ER expansion and increased secretion of the pro-inflammatory mediator IL6 were partly reversed by silencing ATF6α in senescent cells. Moreover, ATF6α drives the increase of senescence associated-β-galactosidase activity. Collectively, these findings unveil a novel and central role for ATF6α in the establishment of morphological features of senescence in normal human primary fibroblasts.


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