title: COX-2-independent effects of celecoxib sensitize lymphoma B cells to TRAIL-mediated apoptosis.
abstract: OBJECTIVE
  Despite therapeutic advances, non-Hodgkin lymphomas (NHL) remain incurable. They form a group of neoplasms strongly dependent on their inflammatory microenvironment, which plays an important supportive role in tumor B-cell survival and in the resistance to antitumor immune response. New therapies must consider both tumor cells and their surrounding microenvironment
  
  
  METHODS
  Stromal cells, derived from bone marrow or lymph nodes, and B cells from follicular lymphoma patients were cocultured or cultured alone with celecoxib treatment, a nonsteroidal anti-inflammatory drug, and/or TRAIL, a promising cytotoxic molecule for cancer therapy.
  
  
  RESULTS
  In this study, we show that follicular lymphoma stromal cells produce large amounts of PGE2. This production is abrogated after celecoxib treatment, targeting the COX-2 isoenzyme involved in PGE2 synthesis. Furthermore, we demonstrate that celecoxib increases apoptosis in NHL B-cell lines and in primary follicular lymphoma B cells cocultured with stromal cells, but independently of the PGE2/COX-2 axis. Finally, celecoxib increases the apoptotic activity of TRAIL. We provide evidence that celecoxib affects proliferation and sensitizes NHL B-cell lines to apoptosis through COX-2-independent effects by slowing down the cell cycle and decreasing the expression of survival proteins, such as Mcl-1.
  
  
  CONCLUSIONS
  These data suggest new potent strategies for NHL therapy combining drugs targeting both tumor B cells and survival signals provided by the tumor microenvironment.
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Gallouet
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Travert
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bresson-Bepoldin
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guilloton
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Pangault
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Caulet-Maugendre
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: Authors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, FranceAuthors' Affiliations: INSERM, UMR 917; Université Rennes 1; EFS Bretagne; Centre Hospitalier Universitaire (CHU), Service d'Hématologie; Biosit, SFR Biologie-Santé, Rennes; INSERM, U955, Créteil; and INSERM, U916, Bordeaux, France thierry.guillaudeux@univ-rennes1.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Guillaudeux
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D052246:Cyclooxygenase 2 Inhibitors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011720:Pyrazoles; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; D051028:bcl-2-Associated X Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone