Blood Journal
Leading the way in experimental and clinical research in hematology

Induction of Ca2+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2–IP3 receptor interaction

  1. Fei Zhong1,*,
  2. Michael W. Harr1,*,
  3. Geert Bultynck2,
  4. Giovanni Monaco2,
  5. Jan B. Parys2,
  6. Humbert De Smedt2,
  7. Yi-Ping Rong1,
  8. Jason K. Molitoris1,
  9. Minh Lam3,
  10. Christopher Ryder1,
  11. Shigemi Matsuyama1, and
  12. Clark W. Distelhorst1
  1. 1Departments of Medicine and Pharmacology, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, and University Hospitals Case Medical Center, Cleveland, OH;
  2. 2Laboratory of Molecular and Cellular Signalling, Department of Molecular and Cellular Biology, K.U. Leuven Campus Gasthuisberg, Leuven, Belgium; and
  3. 3Department of Dermatology, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, and University Hospitals Case Medical Center, Cleveland, OH

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 IP3-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.

  • Submitted September 14, 2010.
  • Accepted December 12, 2010.
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