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Review
. 2018 Nov;1865(11 Pt B):1795-1804.
doi: 10.1016/j.bbamcr.2018.07.020. Epub 2018 Jul 25.

_targeting Bcl-2-IP3 receptor interaction to treat cancer: A novel approach inspired by nearly a century treating cancer with adrenal corticosteroid hormones

Clark W Distelhorst  1
Affiliations
Review

_targeting Bcl-2-IP3 receptor interaction to treat cancer: A novel approach inspired by nearly a century treating cancer with adrenal corticosteroid hormones

Clark W Distelhorst. Biochim Biophys Acta Mol Cell Res. 2018 Nov.

Abstract

Bcl-2 inhibits cell death by at least two different mechanisms. On the one hand, its BH3 domain binds to pro-apoptotic proteins such as Bim and prevents apoptosis induction. On the other hand, the BH4 domain of Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (IP3R), preventing Ca2+ signals that mediate cell death. In normal T-cells, Bcl-2 levels increase during the immune response, protecting against cell death, and then decline as apoptosis ensues and the immune response dissipates. But in many cancers Bcl-2 is aberrantly expressed and exploited to prevent cell death by inhibiting IP3R-mediated Ca2+ elevation. This review summarizes what is known about the mechanism of Bcl-2's control over IP3R-mediated Ca2+ release and cell death induction. Early insights into the role of Ca2+ elevation in corticosteroid-mediated cell death serves as a model for how _targeting IP3R-mediated Ca2+ elevation can be a highly effective therapeutic approach for different types of cancer. Moreover, the successful development of ABT-199 (Venetoclax), a small molecule _targeting the BH3 domain of Bcl-2 but without effects on Ca2+, serves as proof of principle that _targeting Bcl-2 can be an effective therapeutic approach. BIRD-2, a synthetic peptide that inhibits Bcl-2-IP3R interaction, induces cell death induction in ABT-199 (Venetoclax)-resistant cancer models, attesting to the value of developing therapeutic agents that selectively _target Bcl-2-IP3R interaction, inducing Ca2+-mediated cell death.

Keywords: Adrenal corticosteroid hormones; Apoptosis; Bcl-2; Calcium (Ca(2+)); Dexamethasone; Endoplasmic reticulum; Inositol 1,4,5-trisphosphate receptor (IP(3)R); Prednisone.

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Conflict of interest statement

Conflict of Interest

There is no conflict of interest, either financially or otherwise. There are not duplicate articles submitted or published elsewhere.

Figures

Figure 1.
Figure 1.. B-cell receptor (BCR) signaling pathways important to the pathophysiology and treatment options for chronic lymphocytic leukemia (CLL).
A critical step in BCR signaling is Bruton’s tyrosine kinase (BTK) which feeds forward into IP3 receptor-mediated Ca2+ release from the ER (left side of figure) and through the Ras-Raf-Mek-Erk pathway (right side of figure). The Bcl-2 protein is located on both the ER and mitochondria where it regulates Ca2+ signals important in generating a variety of light and death decisions.
Figure 2.
Figure 2.. Bcl-2 and T-cell responses in the immune response.
T-cell levels of Bcl-2 vary during T-cell development, allowing for negative selection in the thymic cortex and facilitating positive selection in the thymic medulla. High levels of Bcl-2 insure cell survival during the immune response, then decline as apoptosis allows the immune response to decline.
Figure 3.
Figure 3.. Bcl-2-IP3R interacting sites and derivation of BIRD-2.
The BH4 domain of Bcl-2 binds to IP3R domain 3 (red) and a region near domain 6 (green). BIRD-2 is a 20 amino acid synthetic peptide based on a coiled coil region in IP3R domain 3, with a DD/AA mutation introduced to block a protease cleavage site. BIRD-2 binds to the BH4 domain of Bcl-2 and functions as a decoy peptide, inhibiting Bcl-2-IP3R interaction and inducing cell death in Bcl-2-positive malignancies.
Figure 4.
Figure 4.. _targeting Bcl-2’s dual anti-apoptotic mechanisms.
(A) The decoy peptide BIRD-2 binds to the BH4 domain of Bcl-2, whereas the small molecule ABT-199/Venetoclax binds to the BH3 domain of Bcl-2. (B) Left: Bcl-2 binds via its BH4 domain to IP3Rs, preventing excessive IP3R-mediated Ca2+ elevation, thereby inhibiting Ca2+ induced apoptosis. BIRD-2 binds to the BH4 domain of Bcl-2, disrupting Bcl-2-IP3R interaction and thus inducing high amplitude Ca2+ elevation that triggers apoptosis. Right: The BH3 region of Bcl-2 binds and sequesters the pro-apoptotic protein Bim, preventing Bim-mediated apoptosis. ABT-199 (Venetoclax) displaces Bim, thus triggering Bim-mediated apoptosis.
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