title: Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS).
abstract: Melanoma cells can enter the process of senescence, but whether they express a secretory phenotype, as reported for other cells, is undetermined. This is of paramount importance, because this secretome can alter the tumor microenvironment and the response to chemotherapeutic drugs. More generally, the molecular events involved in formation of the senescent-associated secretome have yet to be determined. We reveal here that melanoma cells experiencing senescence in response to diverse stimuli, including anti-melanoma drugs, produce an inflammatory secretory profile, where the chemokine ligand-2 (CCL2) acts as a critical effector. Thus, we reveal how senescence induction might be involved in therapeutic failure in melanoma. We further provide a molecular relationship between senescence induction and secretome formation by revealing that the poly(ADP-ribose) polymerase-1 (PARP-1)/nuclear factor-κB (NF-κB) signaling cascade, activated during senescence, drives the formation of a secretome endowed with protumoral and prometastatic properties. Our findings also point to the existence of the PARP-1 and NF-κB-associated secretome, termed the PNAS, in nonmelanoma cells. Most importantly, inhibition of PARP-1 or NF-κB prevents the proinvasive properties of the secretome. Collectively, identification of the PARP-1/NF-κB axis in secretome formation opens new avenues for therapeutic intervention against cancers.
authors.affiliation: Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Equipe labellisée Ligue Nationale contre le Cancer, Nice, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ohanna
authors.forename: Sandy
authors.initials: S
authors.lastname: Giuliano
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonet
authors.forename: Véronique
authors.initials: V
authors.lastname: Imbert
authors.forename: Véronique
authors.initials: V
authors.lastname: Hofman
authors.forename: Joséphine
authors.initials: J
authors.lastname: Zangari
authors.forename: Karine
authors.initials: K
authors.lastname: Bille
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rocchi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Peyron
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lacour
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence; D018932:Chemokine CCL2 / Q000378:metabolism; D004249:DNA Damage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases