Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

• DOI: 10.1038/s41418-018-0142-3
• Publication Date: 2018-06-13T10:33:21Z
• Authors: Mart Bittremieux; Rita M. La Rovere; Haidar Akl; Claudio Martines; Kirsten Welkenhuyzen; Kathia Dubron; Myriam Baes; Ann Janssens; Peter Vandenberghe; Luca Laurenti; Katja Rietdorf; Giampaolo Morciano; Paolo Pinton; Katsuhiko Mikoshiba; Martin D. Bootman; Dimitar G. Efremov; Humbert De Smedt; Jan B. Parys; Geert Bultynck
• Keywords: Inositol trisphosphate receptor

Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated Ca2+-signaling. A peptide tool (Bcl-2/IP3R Disruptor-2; BIRD-2) was developed to abrogate the interaction of with IP3Rs targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death primary CLL cells DLBCL lines. Particularly, high levels IP3R2 were sensitive BIRD-2. Here, we report that BIRD-2-induced does not only depend on IP3R2-expression levels, but also constitutive IP3 signaling, downstream tonically active receptor. The basal Ca2+ level SU-DHL-4 significantly elevated due production. This signaling fulfilled a pro-survival role, since inhibition phospholipase C (PLC) using U73122 (2.5 µM) caused cells. Milder lower concentration (1 or expression an sponge suppressed both elevation apoptosis Basal PLC/IP3 role other lines, Karpas 422, RI-1 SU-DHL-6 cells, whereas PLC protected these against BIRD-2-evoked apoptosis. Finally, treatment CLL, unsupported systems co-cultures CD40L-expressing fibroblasts. Thus, is important for cancer survival, represents vulnerability, rendering dependent limit IP3R activity. seems switch from into pro-death, presenting plausible therapeutic strategy.