Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor

Department of Medicine, Comprehensive Cancer Center and University Hospital of Cleveland, Case Western Reserve University, Cleveland, OH 44106, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 12/2008; 1793(6):971-8. DOI: 10.1016/j.bbamcr.2008.10.015
Source: PubMed


Bcl-2 is the founding member of a large family of apoptosis regulating proteins. Bcl-2 is a prime target for novel therapeutics because it is elevated in many forms of cancer and contributes to cancer progression and therapy resistance based on its ability to inhibit apoptosis. Bcl-2 interacts with proapoptotic members of the Bcl-2 family to inhibit apoptosis and small molecules that disrupt this interaction have already entered the cancer therapy arena. A separate function of Bcl-2 is to inhibit Ca2+ signals that promote apoptosis. This function is mediated through interaction of the Bcl-2 BH4 domain with the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel. A novel peptide inhibitor of this interaction enhances proapoptotic Ca2+ signals. In preliminary experiments this peptide enhanced ABT-737 induced apoptosis in chronic lymphocytic leukemia cells. These findings draw attention to the BH4 domain as a potential therapeutic target. This review summarizes what is currently known about the BH4 domain of Bcl-2, its interaction with the IP3R and other proteins, and the part it plays in Bcl-2's anti-apoptotic function. In addition, we speculate on how the BH4 domain of Bcl-2 can be targeted therapeutically not only for diseases associated with apoptosis resistance, but also for diseases associated with accelerated cell death.

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Available from: Yiping Rong, Nov 10, 2014
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    • "erload . Consistent with this al - ternate model a peptide derived from IP3R has been shown to disrupt the BCL - 2 / IP3R inter - action and reverse the inhibitory effect of BCL - 2 on IP3R ( Rong et al . 2008 ) . The inhibitory effect of BCL - 2 was attributed to the BH4 do - main of BCL - 2 that binds the regulatory and coupling domain of IP3R ( Rong et al . 2009 ) ."
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    ABSTRACT: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
    Cold Spring Harbor perspectives in biology 02/2013; 5(2). DOI:10.1101/cshperspect.a008722 · 8.68 Impact Factor
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    • "Bcl-2 family proteins are involved in this process, as several members, including Mcl-1, have been shown to interact with e.g. inositol 1,4,5-triphosphate receptor [34]–[38]. The precise mechanisms how the 9.2.27PE+ABT-737 drug combination causes calcium release and synergistic cell death in melanoma cells is under investigation. "
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    ABSTRACT: In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE)-based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA) enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination.
    PLoS ONE 09/2011; 6(9):e24012. DOI:10.1371/journal.pone.0024012 · 3.23 Impact Factor
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    • "An alternative strategy could be presented by targeting Ca 2+ signaling as a mediator of Ca 2+ -dependent cell death [55] [56]. In this respect different types of Ca 2+ transporters [57], particularly IP 3 Rs [58] and some types of TRP channels [59] may play an important role. Different contributions in this Special Issue particularly by C. Distelhorst and M. Bootman, and by N. Prevarskaya and colleagues, deal with different aspects of cell death in cancer pathology. "
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    ABSTRACT: Ca(2+) regulates many steps in cell death mechanisms, and is potentially involved in all types of cell death. Moreover, virtually all elements of the cellular Ca(2+) toolbox seem to contribute to remodeling of the Ca(2+) signaling machinery during cell death processes. As expected from the ubiquitous nature of Ca(2+) signaling, these mechanisms are operative in all cell types, and their malfunction may lead to a wide diversity of pathological implications. The contributions in this Special Issue deal with many different aspects of the relation between Ca(2+) signaling and cell death. They illustrate the complexity of this relation, and importantly they give an outlook on potential new therapeutic targets for treatment of diseases connected to defects in cell death pathways.
    Cell calcium 07/2011; 50(3):207-10. DOI:10.1016/j.ceca.2011.06.004 · 3.51 Impact Factor
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