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

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2011 Jan 4

PMID 21193695

Citations 62

Authors

Fei Zhong

Michael W Harr

Geert Bultynck

Giovanni Monaco

Jan B Parys

Humbert De Smedt

Yi-Ping Rong

Jason K Molitoris

Minh Lam

Christopher Ryder

Shigemi Matsuyama

Clark W Distelhorst

Affiliations

Soon will be listed here.

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.

Citing Articles

The Complex Effects of PKM2 and PKM2:IPR Disruption on Intracellular Ca Handling and Cellular Functions.

Lemos F, de Ridder I, Bootman M, Bultynck G, Parys J Cells. 2023; 12(21).

PMID: 37947604 PMC: 10647343. DOI: 10.3390/cells12212527.

Calcium's Role in Orchestrating Cancer Apoptosis: Mitochondrial-Centric Perspective.

Moon D Int J Mol Sci. 2023; 24(10).

PMID: 37240331 PMC: 10218825. DOI: 10.3390/ijms24108982.

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential.

Immanuel T, Li J, Green T, Bogdanova A, Kalev-Zylinska M Front Oncol. 2022; 12:1010506.

PMID: 36330491 PMC: 9623116. DOI: 10.3389/fonc.2022.1010506.

A cellular atlas of calcineurin signaling.

Ulengin-Talkish I, Cyert M Biochim Biophys Acta Mol Cell Res. 2022; 1870(1):119366.

PMID: 36191737 PMC: 9948804. DOI: 10.1016/j.bbamcr.2022.119366.

iRhom pseudoproteases regulate ER stress-induced cell death through IP receptors and BCL-2.

Dulloo I, Atakpa-Adaji P, Yeh Y, Levet C, Muliyil S, Lu F Nat Commun. 2022; 13(1):1257.

PMID: 35273168 PMC: 8913617. DOI: 10.1038/s41467-022-28930-4.

References

Contri A, Brunati A, Trentin L, Cabrelle A, Miorin M, Cesaro L . Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest. 2005; 115(2):369-78. PMC: 544036. DOI: 10.1172/JCI22094. View

Rong Y, Bultynck G, Aromolaran A, Zhong F, Parys J, De Smedt H . The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci U S A. 2009; 106(34):14397-402. PMC: 2728114. DOI: 10.1073/pnas.0907555106. View

Pacher P, Hajnoczky G . Propagation of the apoptotic signal by mitochondrial waves. EMBO J. 2001; 20(15):4107-21. PMC: 149166. DOI: 10.1093/emboj/20.15.4107. View

Palmer A, Jin C, Reed J, Tsien R . Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc Natl Acad Sci U S A. 2004; 101(50):17404-9. PMC: 535104. DOI: 10.1073/pnas.0408030101. View

Chipuk J, Moldoveanu T, Llambi F, Parsons M, Green D . The BCL-2 family reunion. Mol Cell. 2010; 37(3):299-310. PMC: 3222298. DOI: 10.1016/j.molcel.2010.01.025. View

Zhong F, Davis M, McColl K, Distelhorst C . Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation. J Cell Biol. 2006; 172(1):127-37. PMC: 2063540. DOI: 10.1083/jcb.200506189. View

Cardenas C, Miller R, Smith I, Bui T, Molgo J, Muller M . Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell. 2010; 142(2):270-83. PMC: 2911450. DOI: 10.1016/j.cell.2010.06.007. View

Berridge M, Bootman M, Roderick H . Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003; 4(7):517-29. DOI: 10.1038/nrm1155. View

Orrenius S, Zhivotovsky B, Nicotera P . Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003; 4(7):552-65. DOI: 10.1038/nrm1150. View

10.

Giacomello M, Drago I, Pizzo P, Pozzan T . Mitochondrial Ca2+ as a key regulator of cell life and death. Cell Death Differ. 2007; 14(7):1267-74. DOI: 10.1038/sj.cdd.4402147. View

11.

Kitada S, Andersen J, Akar S, Zapata J, Takayama S, Krajewski S . Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood. 1998; 91(9):3379-89. View

12.

Vogler M, Dinsdale D, Sun X, Young K, Butterworth M, Nicotera P . A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells. Cell Death Differ. 2008; 15(5):820-30. DOI: 10.1038/cdd.2008.25. View

13.

Csordas G, Renken C, Varnai P, Walter L, Weaver D, Buttle K . Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol. 2006; 174(7):915-21. PMC: 2064383. DOI: 10.1083/jcb.200604016. View

14.

Yip K, Reed J . Bcl-2 family proteins and cancer. Oncogene. 2008; 27(50):6398-406. DOI: 10.1038/onc.2008.307. View

15.

Cimmino A, Calin G, Fabbri M, Iorio M, Ferracin M, Shimizu M . miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005; 102(39):13944-9. PMC: 1236577. DOI: 10.1073/pnas.0506654102. View

16.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

17.

Chen R, Valencia I, Zhong F, McColl K, Roderick H, Bootman M . Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J Cell Biol. 2004; 166(2):193-203. PMC: 2172311. DOI: 10.1083/jcb.200309146. View

18.

Bezprozvanny I . The inositol 1,4,5-trisphosphate receptors. Cell Calcium. 2005; 38(3-4):261-72. DOI: 10.1016/j.ceca.2005.06.030. View

19.

Szalai G, Krishnamurthy R, Hajnoczky G . Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J. 1999; 18(22):6349-61. PMC: 1171698. DOI: 10.1093/emboj/18.22.6349. View

20.

Cozma D, Yu D, Hodawadekar S, Azvolinsky A, Grande S, Tobias J . B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling. J Clin Invest. 2007; 117(9):2602-10. PMC: 1950455. DOI: 10.1172/JCI30842. View