BH3-only protein BIM: An emerging target in chemotherapy

Abstract

BH3-only proteins constitute major proportion of pro-apoptotic members of B-cell lymphoma 2 (Bcl-2) family of apoptotic regulatory proteins and participate in embryonic development, tissue homeostasis and immunity. Absence of BH3-only proteins contributes to autoimmune disorders and tumorigenesis. Bim (Bcl-2 Interacting Mediator of cell death), most important member of BH3-only proteins, shares a BH3-only domain (9–16 aa) among 4 domains (BH1-BH4) of Bcl-2 family proteins and highly pro-apoptotic in nature. Bim initiates the intrinsic apoptotic pathway under both physiological and patho-physiological conditions. Reduction in Bim expression was found to be associated with tumor promotion and autoimmunity, while overexpression inhibited tumor growth and drug resistance as cancer cells suppress Bim expression and stability. Apart from its role in normal homeostasis, Bim has emerged as a central player in regulation of tumorigenesis, therefore gaining attention as a plausible target for chemotherapy. Regulation of Bim expression and stability is complicated and regulated at multiple levels viz. transcriptional, post-transcriptional, post-translational (preferably by phosphorylation and ubiquitination), epigenetic (by promoter acetylation or methylation) including miRNAs. Furthermore, control over Bim expression and stability may be exploited to enhance chemotherapeutic efficacy, overcome drug resistance and select anticancer drug regimen as various chemotherapeutic agents exploit Bim as an executioner of cell death. Owing to its potent anti-tumorigenic activity many BH3 mimetics e.g. ABT-737, ABT-263, obatoclax, AT-101and A-1210477 have been developed and entered in clinical trials. It is more likely that in near future strategies commanding Bim expression and stability ultimately lead to Bim based therapeutic regimen for cancer treatment.