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Disrupting inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R)/B-cell lymphoma 2 (Bcl-2) complexes using a cell-permeable peptide (stabilized TAT-fused IP 3 R-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 IP 3 R/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 IP 3 R-mediated Ca 2+  release. Although total IP 3 R-expression levels were very similar among SU-DHL-4 and OCI-LY-1, we discovered that the IP 3 R2-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 IP 3 R2-protein level, but not with IP 3 R1-, IP 3 R3- or total IP 3 R-expression levels. Inhibiting or knocking down IP 3 R2 activity in SU-DHL-4-reduced TAT-IDP S -induced apoptosis, which is compatible with its ability to dissociate Bcl-2 from IP 3 R2 and to promote IP 3 -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 IP 3 R hyperactivity. In particular, cancer cells expressing high levels of IP 3 R2 are addicted to IP 3 R/Bcl-2 complex formation and disruption of these complexes using peptide tools results in pro-apoptotic Ca 2+  signaling and cell death.

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