학술논문
Blocking Orai1 constitutive activity inhibits B-cell cancer migration and synergistically acts with drugs to reduce B-CLL cell survival.
Document Type
Academic Journal
Author
Scaviner J; INSERM UMR1227, Université de Bretagne Occidentale, F-29200 Brest, France.; Bagacean C; INSERM UMR1227, Université de Bretagne Occidentale, F-29200 Brest, France.; Christian B; INSERM UMR1227, Université de Bretagne Occidentale, F-29200 Brest, France.; Renaudineau Y; INSERM UMR1227, Université de Bretagne Occidentale, F-29200 Brest, France.; Mignen O; INSERM UMR1227, Université de Bretagne Occidentale, F-29200 Brest, France.; Abdoul-Azize S; INSERM UMR1227, Université de Bretagne Occidentale, F-29200 Brest, France. Electronic address: souleymane.abdoul-azize@inserm.fr.
Source
Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
Subject
Language
English
Abstract
Orai1 channel capacity to control store-operated Ca 2+ entry (SOCE) and B-cell functions is poorly understood and more specifically in B-cell cancers, including human lymphoma and leukemia. As compared to normal B-cells, Orai1 is overexpressed in B-chronic lymphocytic leukemia (B-CLL) and contributes in resting B-CLL to mediate an elevated basal Ca 2+ level through a constitutive Ca 2+ entry, and in BCR-activated B-cell to regulate the Ca 2+ signaling response. Such observations were confirmed in human B-cell lymphoma and leukemia lines, including RAMOS, JOK-1, MEC-1 and JVM-3 cells. Next, the use of pharmacological Orai1 inhibitors (GSK-7975 A and Synta66) blocks constitutive Ca 2+ entry and in turn affects B-cell cancer (primary and cell lines) survival and migration, controls cell cycle, and induces apoptosis through a mitochondrial and caspase-3 independent pathway. Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca 2+ channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)