title: Level of macroautophagy drives senescent keratinocytes into cell death or neoplastic evasion.
abstract: Senescence is a non-proliferative state reached by normal cells in response to various stresses, including telomere uncapping, oxidative stress or oncogene activation. In previous reports, we have highlighted that senescent human epidermal keratinocytes have two opposite outcomes: either they die by autophagic programmed cell death or they evade in the form of neoplastic postsenescence emergent (PSNE) cells. Herein, we show that partially reducing macroautophagy in senescent keratinocytes using 3-methyl adenine or anti-Atg5 siRNAs increases the PSNE frequency, suggesting that senescent keratinocytes have to escape autophagic cell death to generate PSNE cells. However, totally inhibiting macroautophagy impairs PSNE and leads to a huge accumulation of oxidative damages, indicating that senescent keratinocytes need to achieve quality-control macroautophagy for PSNE to occur. In accordance, we demonstrate that the progenitors of PSNE cells display a level of macroautophagy slightly lower than that of the average senescent population, which is directly dictated by their level of reactive oxygen species, their level of upregulation of MnSOD, their level of activation of NF-κB transcription factors and their level of dysfunctional mitochondria. Macroautophagy thus has antagonistic roles during senescence, inducing cell death or promoting neoplastic transformation, depending on its level of activation. Taken together, these data suggest that levels of oxidative damages and ensuing macroautophagic activity could be two main determinants of the very initial phases of neoplastic transformation by senescence evasion.
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: E
authors.initials: E
authors.lastname: Deruy
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: J
authors.initials: J
authors.lastname: Nassour
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: N
authors.initials: N
authors.lastname: Martin
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: C
authors.initials: C
authors.lastname: Vercamer
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: N
authors.initials: N
authors.lastname: Malaquin
authors.affiliation: Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertout
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: F
authors.initials: F
authors.lastname: Chelli
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: A
authors.initials: A
authors.lastname: Pourtier
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: O
authors.initials: O
authors.lastname: Pluquet
authors.affiliation: 1] CNRS, UMR8161, Institut de Biologie de Lille, Lille F-59021, France [2] University Lille 1 59650, Villeneuve d'Ascq, France [3] University Lille 2, Lille 59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: C
authors.initials: C
authors.lastname: Abbadie
mesh_terms: D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase