Induction of Ca²+-driven Apoptosis in Chronic Lymphocytic Leukemia Cells by Peptide-Mediated Disruption of Bcl-2-IP3 Receptor Interaction

Blood. 2011 Mar 10;117(10):2924-34. doi: 10.1182/blood-2010-09-307405. Epub 2010 Dec 30.

Abstract

Bcl-2 contributes to the pathophysiology and therapeutic resistance of chronic lymphocytic leukemia (CLL). Therefore, developing inhibitors of this protein based on a thorough understanding of its mechanism of action is an active and promising area of inquiry. One approach centers on agents (eg, ABT-737) that compete with proapoptotic members of the Bcl-2 protein family for binding in the hydrophobic groove formed by the BH1-BH3 domains of Bcl-2. Another region of Bcl-2, the BH4 domain, also contributes to the antiapoptotic activity of Bcl-2 by binding to the inositol 1,4,5-trisphosphate receptor (IP₃R) Ca²(+) channel, inhibiting IP(3)-dependent Ca²(+) release from the endoplasmic reticulum. We report that a novel synthetic peptide, modeled after the Bcl-2-interacting site on the IP₃R, binds to the BH4 domain of Bcl-2 and functions as a competitive inhibitor of the Bcl-2-IP₃R interaction. By disrupting the Bcl-2-IP₃R interaction, this peptide induces an IP₃R-dependent Ca²(+) elevation in lymphoma and leukemia cell lines and in primary CLL cells. The Ca²(+) elevation evoked by this peptide induces apoptosis in CLL cells, but not in normal peripheral blood lymphocytes, suggesting the involvement of the Bcl-2-IP₃R interaction in the molecular mechanism of CLL and indicating the potential merit of targeting this interaction therapeutically.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis / physiology*
  • Binding, Competitive
  • Blotting, Western
  • Calcium / metabolism*
  • Cell Line, Tumor
  • Humans
  • Immunoprecipitation
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Peptides / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*

Substances

  • BIRD-2 peptide
  • Inositol 1,4,5-Trisphosphate Receptors
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • Calcium