title: IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2.
abstract: Disrupting inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)/B-cell lymphoma 2 (Bcl-2) complexes using a cell-permeable peptide (stabilized TAT-fused IP3R-derived peptide (TAT-IDP(S))) that selectively targets the BH4 domain of Bcl-2 but not that of B-cell lymphoma 2-extra large (Bcl-Xl) potentiated pro-apoptotic Ca(2+) signaling in chronic lymphocytic leukemia cells. However, the molecular mechanisms rendering cancer cells but not normal cells particularly sensitive to disrupting IP3R/Bcl-2 complexes are poorly understood. Therefore, we studied the effect of TAT-IDP(S) in a more heterogeneous Bcl-2-dependent cancer model using a set of 'primed to death' diffuse large B-cell lymphoma (DL-BCL) cell lines containing elevated Bcl-2 levels. We discovered a large heterogeneity in the apoptotic responses of these cells to TAT-IDP(S) with SU-DHL-4 being most sensitive and OCI-LY-1 being most resistant. This sensitivity strongly correlated with the ability of TAT-IDP(S) to promote IP3R-mediated Ca(2+) release. Although total IP3R-expression levels were very similar among SU-DHL-4 and OCI-LY-1, we discovered that the IP3R2-protein level was the highest for SU-DHL-4 and the lowest for OCI-LY-1. Strikingly, TAT-IDP(S)-induced Ca(2+) rise and apoptosis in the different DL-BCL cell lines strongly correlated with their IP3R2-protein level, but not with IP3R1-, IP3R3- or total IP3R-expression levels. Inhibiting or knocking down IP3R2 activity in SU-DHL-4-reduced TAT-IDP(S)-induced apoptosis, which is compatible with its ability to dissociate Bcl-2 from IP3R2 and to promote IP3-induced pro-apoptotic Ca(2+) signaling. Thus, certain chronically activated B-cell lymphoma cells are addicted to high Bcl-2 levels for their survival not only to neutralize pro-apoptotic Bcl-2-family members but also to suppress IP3R hyperactivity. In particular, cancer cells expressing high levels of IP3R2 are addicted to IP3R/Bcl-2 complex formation and disruption of these complexes using peptide tools results in pro-apoptotic Ca(2+) signaling and cell death.
authors.affiliation: Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Akl
authors.forename: G
authors.initials: G
authors.lastname: Monaco
authors.forename: R
authors.initials: R
authors.lastname: La Rovere
authors.forename: K
authors.initials: K
authors.lastname: Welkenhuyzen
authors.forename: S
authors.initials: S
authors.lastname: Kiviluoto
authors.forename: T
authors.initials: T
authors.lastname: Vervliet
authors.forename: J
authors.initials: J
authors.lastname: Molgó
authors.forename: C W
authors.initials: CW
authors.lastname: Distelhorst
authors.forename: L
authors.initials: L
authors.lastname: Missiaen
authors.forename: K
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: J B
authors.initials: JB
authors.lastname: Parys
authors.forename: H
authors.initials: H
authors.lastname: De Smedt
authors.forename: G
authors.initials: G
authors.lastname: Bultynck
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D002118:Calcium