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

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 (IPR), preventing Ca 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 IPR-mediated Ca elevation. This review summarizes what is known about the mechanism of Bcl-2's control over IPR-mediated Ca release and cell death induction. Early insights into the role of Ca elevation in corticosteroid-mediated cell death serves as a model for how targeting IPR-mediated Ca 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 Ca, serves as proof of principle that targeting Bcl-2 can be an effective therapeutic approach. BIRD-2, a synthetic peptide that inhibits Bcl-2-IPR 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-IPR interaction, inducing Ca-mediated cell death.

Type 3 Inositol 1,4,5‐Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma

“…SH3BP5 was found to have a significant interaction with the protein‐coding gene of unknown function KIAA0040, so the functional relevance of SH3BP5 up‐regulation in cholangiocytes lacking ITPR3 is less clear. However, SH3BP5 is a known negative regulator of Bruton's tyrosine kinase (BTK), which promotes development of malignancy by enhancing ITPR‐mediated calcium release, and is a substrate of c‐Jun N‐terminal kinase, which suggests that this gene might work by modulating tyrosine kinase signaling in transformed cholangiocytes. No significant interactions were uncovered for AP1S3 by EGAN analysis.…”

“…Indeed, abnormal expression of tumor suppressors that modify this degradation pathway, including BRCA1 associated protein 1 (BAP1) and phosphatase and tensin homolog (PTEN), has been linked to altered ITPR3 and resulting tumor development in several types of malignancies . Alternatively, the antiapoptotic protein BCL2 apoptosis regulator promotes cancer by binding to ITPR to inhibit calcium release into mitochondria, although myeloid cell leukemia 1, which also inhibits mitochondrial calcium, is thought to be a more important antiapoptotic protein in CCA. In each of these cases, however, a decrease rather than an increase in ITPR3 or its activity is thought to contribute to neoplasia because loss of ITPR3 from MAMs can sometimes decrease apoptosis of cancer cells.…”

Creating a New Cancer Therapeutic Agent by Targeting the Interaction between Bcl-2 and IP3Receptors

“…Whatever mechanism is involved in an elevated expression of Bcl-2, numerous studies have shown that part of the ensuing increased cell survival arises because of a modulation of cellular Ca 2+ signaling by Bcl-2 (Distelhorst and Bootman 2011;Greenberg et al 2014;Vervliet et al 2016;Distelhorst 2018). This review proceeds in a chronological manner through the elucidation of Bcl-2/IP 3 R interaction, the modulation of Ca 2+ signaling by Bcl-2, and ends with a discussion of the current development of small molecules that can modify the Bcl-2/IP 3 R interaction and thereby possess therapeutic potential for the treatment of cancer.…”

Lessons from the Endoplasmic Reticulum Ca2+ Transporters—A Cancer Connection

“…Nonetheless, these complexes of anti-apoptotic Bcl-2 proteins and IP 3 R channels may open the door for innovative therapeutic interventions. As a matter of fact, recent years have witnessed the tremendous breakthrough in the use of synthetic peptides to disrupt the Bcl-2-IP 3 R complex in chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma and small cell lung cancer either alone or with other mimetics to potentiate anti-neoplastic effects and / or tackle chemo-resistance [ 109 , 110 , 111 , 112 , 113 ]. On the other end of the spectrum, a growing body of evidence suggests that IP 3 R activity is subject to regulation by tumor suppressors.…”