title: Localized Store-Operated Calcium Influx Represses CD95-Dependent Apoptotic Effects of Rituximab in Non-Hodgkin B Lymphomas.
abstract: The anti-CD20 mAb, rituximab, is routinely used to treat B cell malignancies. However, a majority of patients relapse. An improvement in the complete response was obtained by combining rituximab with chemotherapy, at the cost of increased toxicity. We reported that rituximab induced the colocalization of both the Orai1 Ca(2+) release-activated Ca(2+) channel (CRAC) and the endoplasmic reticulum Ca(2+) sensor stromal interaction molecule 1 with CD20 and CD95 into a cluster, eliciting a polarized store-operated Ca(2+) entry (SOCE). We observed that blocking this Ca(2+) entry with downregulation of Orai1, pharmacological inhibitors, or reducing calcemia with hypocalcemic drugs sensitized human B lymphoma cell lines and primary human lymphoma cells to rituximab-induced apoptosis in vitro, and improved the antitumoral effect of rituximab in xenografted mice. This revealed that Ca(2+) entry exerted a negative feedback loop on rituximab-induced apoptosis, suggesting that associating CRAC channel inhibitors or hypocalcemic agents with rituximab may improve the treatment of patients with B cell malignancies. The calcium-dependent proteins involved in this process appear to vary according to the B lymphoma cell type, suggesting that CRAC-channel targeting is likely to be more efficient than calcium-dependent protein targeting.
authors.affiliation: Institut Bergonié, Centre de Lutte contre le Cancer, F-33076 Bordeaux Cedex, France; Université de Bordeaux, F-33076 Bordeaux Cedex, France; INSERM U916 Validation et Identification de Nouvelles Cibles en Oncologie, F-33076 Bordeaux Cedex, France; laurence.bresson-bepoldin@inserm.fr pierre.vacher@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vacher
authors.affiliation: Institut Bergonié, Centre de Lutte contre le Cancer, F-33076 Bordeaux Cedex, France; Université de Bordeaux, F-33076 Bordeaux Cedex, France; INSERM U916 Validation et Identification de Nouvelles Cibles en Oncologie, F-33076 Bordeaux Cedex, France;
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vacher
authors.affiliation: Animalerie Mutualisée, Université de Bordeaux, F33400 Talence, France;
authors.forename: Raphael
authors.initials: R
authors.lastname: Pineau
authors.affiliation: Institut Bergonié, Centre de Lutte contre le Cancer, F-33076 Bordeaux Cedex, France; Université de Bordeaux, F-33076 Bordeaux Cedex, France; INSERM U916 Validation et Identification de Nouvelles Cibles en Oncologie, F-33076 Bordeaux Cedex, France;
authors.forename: Simon
authors.initials: S
authors.lastname: Latour
authors.affiliation: Institut Bergonié, Centre de Lutte contre le Cancer, F-33076 Bordeaux Cedex, France; Université de Bordeaux, F-33076 Bordeaux Cedex, France; INSERM U916 Validation et Identification de Nouvelles Cibles en Oncologie, F-33076 Bordeaux Cedex, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
authors.affiliation: INSERM, Unité Mixte de Recherche 917, F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Centre Hospitalier Universitaire Pontchaillou, F-35033 Rennes, France;
authors.forename: Celine
authors.initials: C
authors.lastname: Pangault
authors.affiliation: INSERM, Unité Mixte de Recherche 917, F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Centre Hospitalier Universitaire Pontchaillou, F-35033 Rennes, France;
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: Institut Bergonié, Centre de Lutte contre le Cancer, F-33076 Bordeaux Cedex, France; Université de Bordeaux, F-33076 Bordeaux Cedex, France; INSERM U916 Validation et Identification de Nouvelles Cibles en Oncologie, F-33076 Bordeaux Cedex, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Soubeyran
authors.affiliation: Université de Bordeaux, F-33076 Bordeaux Cedex, France; Centre de Recherche Cardio-Thoracique de Bordeaux, F-33076 Bordeaux Cedex, France; and INSERM, U1045, F-33076 Bordeaux Cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ducret
authors.affiliation: Institut Bergonié, Centre de Lutte contre le Cancer, F-33076 Bordeaux Cedex, France; Université de Bordeaux, F-33076 Bordeaux Cedex, France; INSERM U916 Validation et Identification de Nouvelles Cibles en Oncologie, F-33076 Bordeaux Cedex, France; laurence.bresson-bepoldin@inserm.fr pierre.vacher@inserm.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bresson-Bepoldin
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D034622:RNA Interference; D000069283:Rituximab / Q000008:administration & dosage / Q000494:pharmacology*; D000071737:Stromal Interaction Molecule 1; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D018951:Antigens, CD20; D000970:Antineoplastic Agents; D015220:Calcium Channels; D004164:Diphosphonates; C491901:FAS protein, human; D007093:Imidazoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D019014:fas Receptor; D000069283:Rituximab; D000077211:Zoledronic Acid; D002118:Calcium