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

Distelhorst, Clark W. and Bootman, Martin (2019). Creating a New Cancer Therapeutic Agent by Targeting the Interaction between Bcl-2 and IP. Cold Spring Harbor Perspectives in Biology, 11(9)

DOI: https://doi.org/10.1101/cshperspect.a035196

Abstract

Bcl-2 is a member of a family of proteins that regulate cell survival. Expression of Bcl-2 is aberrantly elevated in many types of cancer. Within cells of the immune system, Bcl-2 has a physiological role in regulating immune responses. However, in cancers arising from cells of the immune system Bcl-2 promotes cell survival and proliferation. This review summarizes discoveries over the past 30 years that have elucidated Bcl-2's role in the normal immune system, including its actions in regulating calcium (Ca²⁺) signals necessary for the immune response, and for Ca²⁺ -mediated apoptosis at the end of an immune response. How Bcl-2 modulates the release of Ca²⁺ from intracellular stores via inositol 1,4,5-trisphosphate receptors (IP₃R) is discussed, and in particular, the role of Bcl-2/IP₃R interactions in promoting the survival of cancer cells by preventing Ca²⁺ -mediated cell death. The development and usage of a peptide, referred to as TAT-Pep8, or more recently, BIRD-2, that induces death of cancer cells by inhibiting Bcl-2's control over IP₃R-mediated Ca²⁺ elevation is discussed. Studies aimed at discovering a small molecule that mimics BIRD-2's anticancer mechanism of action are summarized, along with the prospect of such a compound becoming a novel therapeutic option for cancer.

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