HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

Haidar Akl; Rita M.L. La Rovere; Ann Janssens; Peter Vandenberghe; Jan B. Parys; Geert Bultynck

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HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

Haidar Akl ^[1] ; Rita M.L. La Rovere ^[1] ; Ann Janssens ^[2] ; Peter Vandenberghe ^[1] ; Jan B. Parys ^[1] ; Geert Bultynck ^[1]
1. [1] KU Leuven
  
  KU Leuven
  
  Arrondissement Leuven, Bélgica
2. [2] UZ Leuven, Bélgica
Localización: International journal of developmental biology, ISSN 0214-6282, Vol. 59, Nº. Extra 7-9, 2015 (Ejemplar dedicado a: Ionic Messengers in Development and Cancer), págs. 391-398
Idioma: inglés
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Resumen
- Anti-apoptotic B-cell lymphoma 2 (Bcl-2) is commonly upregulated in hematological cancers, including B-cell chronic lymphocytic leukemia (B-CLL) and diffuse large B-cell lymphoma (DLBCL), thereby protecting neoplastic cells from oncogenic-stress-induced apoptosis. Bcl-2 executes its anti-apoptotic function at two different sites in the cell. At the mitochondria, Bcl-2 via its hydrophobic cleft interacts with pro-apoptotic Bcl-2 family members to inhibit apoptosis. At the endoplasmic reticulum (ER), Bcl-2 via its Bcl-2 homology (BH)4 domain, prevents excessive Ca2+ signals by interacting with the inositol 1,4,5-trisphosphate receptor (IP3R), an intracellular Ca2+-release channel. A peptide tool (BIRD-2) that targets the BH4 domain of Bcl-2 reverses Bcl-2’s inhibitory action on IP3Rs and can trigger pro-apoptotic Ca2+ signals in B-cell cancer cells. Here, we explored whether HA14-1, a Bcl-2 inhibitor that also inhibits sarco/endoplasmic reticulum Ca2+-ATPases (SERCA), could potentiate BIRD-2-induced cell death. We measured apoptosis in Annexin V/7-AAD stained cells using flow cytometry and intracellular Ca2+ signals in Fura2-AM-loaded cells using an automated fluorescent plate reader. HA14-1 potentiated BIRD-2-induced Ca2+ release from the ER and apoptosis in both BIRD-2-sensitive DLBCL cell lines (SU-DHL-4) and in primary B-CLL cells. BIRD-2-resistant DLBCL cells (OCI-LY-1) were already very sensitive to HA14-1. Yet, although BIRD-2 moderately increased Ca2+ levels in HA14-1-treated cells, apoptosis was not potentiated by BIRD-2 in these cells. These results further underpin the relevance of IP3R-mediated Ca2+ signaling as a therapeutic target in the treatment of Bcl-2-dependent B-cell malignancies and the advantage of combination regimens with HA14-1 to enhance BIRD-2-induced cell death.