title: Induction of Ca²+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2-IP3 receptor interaction.
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.
authors.affiliation: Department of Medicine and Pharmacology, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, and University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhong
authors.forename: Michael W
authors.initials: MW
authors.lastname: Harr
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monaco
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Rong
authors.forename: Jason K
authors.initials: JK
authors.lastname: Molitoris
authors.forename: Minh
authors.initials: M
authors.lastname: Lam
authors.forename: Christopher
authors.initials: C
authors.lastname: Ryder
authors.forename: Shigemi
authors.initials: S
authors.lastname: Matsuyama
authors.forename: Clark W
authors.initials: CW
authors.lastname: Distelhorst
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001667:Binding, Competitive; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: C000609867:BIRD-2 peptide; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D002118:Calcium