Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS) (original) (raw)

  1. Sandy Giuliano1,2,
  2. Caroline Bonet1,2,
  3. Véronique Imbert2,3,
  4. Véronique Hofman2,4,5,
  5. Joséphine Zangari1,2,
  6. Karine Bille1,2,
  7. Caroline Robert6,
  8. Brigitte Bressac-de Paillerets7,
  9. Paul Hofman2,4,5,
  10. Stéphane Rocchi1,2,8,
  11. Jean-François Peyron2,3,9,10,
  12. Jean-Philippe Lacour8,
  13. Robert Ballotti1,2,8 and
  14. Corine Bertolotto1,2,8,11
  15. 1INSERM, U895, Equipe 1, Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Equipe labellisée Ligue Nationale contre le Cancer, Nice F-06204, France;
  16. 2Université of Nice Sophia-Antipolis, UFR Médecine, Nice F-06107, France;
  17. 3INSERM, U895, Equipe 4, Inflammation, Cancer, Cancer Stem Cells, Nice F-06204, France;
  18. 4INSERM, ERI21/EA 4319, Nice F-06107, France;
  19. 5Human Biobank, Centre Hospitalier Universitaire de Nice, Nice F-06204, France;
  20. 6Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif Cedex 94805, France;
  21. 7Département de Biopathologie, Institut de Cancérologie Gustave Roussy, Villejuif Cedex 94805, France;
  22. 8Service de Dermatologie, Centre Hospitalier Universitaire de Nice, Nice F-06204, France;
  23. 9Service d'Hématologie, Centre Hospitalier Universitaire de Nice, Nice F-06204, France ;
  24. 10Sevice de Pédiatrie, Centre Hospitalier Universitaire de Nice, Nice F-06204, France

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.

Footnotes