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bcl-2

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Official Full Name
B-cell CLL/lymphoma 2
Background
This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Two transcript variants, produced by alternate splicing, differ in their C-terminal ends.
Synonyms
BCL2; B-cell CLL/lymphoma 2; Bcl-2; apoptosis regulator Bcl-2; PCKBCL2

Apoptosis is a physiological process of programmed cell death that maintains tissue function and homeostasis. Apoptosis is regulated by two major pathways: the extrinsic/death receptor pathway and the intrinsic/mitochondrial pathway. The exogenous apoptotic pathway is triggered by ligand-receptor interactions between tumor necrosis factor (TNF) family members and the corresponding transmembrane death receptor. After ligand binding, the adaptor protein is recruited and binds to the death receptor, resulting in activation of downstream caspase cascades and ultimately cell death. The intrinsic apoptosis pathway is mediated by the B cell lymphoma 2 (BCL2) family of proteins.

The BCL2 family, whose namesake was initially identified due to chromosomal translocations that activated BCL2 gene expression, has been identified through their composition of a series of shared BCL2 homology (BH) motifs (BH1, BH2, BH3, and BH4). Importantly, only the BH3 motif, which mediates protein-protein interactions between family members, is strictly conserved across all family members. These proteins are divided into three major subfamilies based on their function and structure: the anti-apoptotic BCL2 proteins, the pro-apoptotic effectors, and the pro-apoptotic BH3 only proteins. The BH3 proteins can be classified into direct activators and sensitizers based on their binding ability to other BCL2 family members. The direct activator BH3 only proteins can interact with both the anti-apoptotic BCL2 proteins and the effectors BAK/BAX while the sensitizer BH3 only proteins preferentially bind to the anti-apoptotic BCL2 proteins and thereby indirectly activate BAK/BAX. Cell fate is determined by the balance between the pro-apoptotic cells and the activity of anti-apoptotic BCL-2 family members. At normal cellular homeostasis, anti-apoptotic members bind directly to the effector BAK/BAX to counteract their ability to induce apoptosis. However, only BH3 members are activated after cellular stress, such as by radiation or treatment with induced cellular stress by cytotoxic agents. These in turn directly activate BAK/BAX and/or neutralize the function of the anti-apoptotic BCL2 family members by competing for their binding with BAK/BAX. As a result, the effectors BAK/BAX oligomerize in the mitochondrial outer membrane and form pores. The resulting mitochondrial outer membrane permeabilization (MOMP) results in cytochrome c release, activation of downstream caspases, and finally cell death. In addition to their regulation of mitochondrial apoptosis, mediated by the crosstalk among BCL2 family members, BCL2 family proteins have also been shown to induce apoptosis via their regulation of Ca2+ signaling.

Fig. 1. BCL2 family mediated intrinsic apoptosis signaling. (Jia et al. Int. J. Mol. Sci. 2018).

A promising cancer therapeutic target

BCL2 antisense oligonucleotide downregulates the anti-apoptotic BCL2 family proteins by targeting the open reading frame of BCL2 gene leading to mRNA degradation. Interestingly, this antisense sequences have been reported to increase the efficiency, when used in combination with other drugs and radiation in mouse tumor models. Synergistic effects of Genasense and dacarbazine on melanoma treatment have been tested. However, it did not show a significant effect on patients with advanced melanoma. Peptide sequences mimicking BH3-only proteins, bind to BCL2 with a higher affinity than pro-apoptotic proteins, thus interfering with their interaction. The free pro-apoptotic proteins can then homodimerize and trigger apoptotic cascades. Peptides derived from the BH3 domain have been shown to inhibit BAX-BCL2 heterodimer formation in vitro. However, the use of such peptides is limited in scope due to their metabolic instability, degradation due to cellular proteases and poor cell permeability, and bioavailability. As reported, a peptide derived from Nur77, a nuclear receptor transfer from nucleus to mitochondria upon cell death stimuli was utilized. In a normal scenario, Nur77 binds to BCL2 at the flexible loop domain and induces conformational changes, converting it from antiapoptotic to proapoptotic protein.

There are many small molecule inhibitors disrupt the interaction between anti-apoptotic BCL-2 heterodimeric complexes and their pro-apoptotic partners BAK/BAX have been developed and investigated extensively. BAK / BAX inserts its BH3 domain into the hydrophobic groove of BCL2 formed by its BH1-4 domain. Therefore, BH3 mimicking SMI works by eliminating the BCL2 and BAK/BAX interactions. Gossypol is a natural phenolic compound found in cotton plants, it has been shown to inhibit apoptosis in mouse tumor models. AT101 is a synthetic derivative of Gossypol that binds to BCL2, BCL-xL, and MCL1. Although, AT101 has been demonstrated to synergistically enhance radiation induced apoptosis, its low target binding affinity and toxic side effects have led to its failure to be developed as a single agent in clinical trials. ABT737 was discovered using high throughput nuclear magnetic resonance (NMR) screening and exhibited high binding affinity for BCL2, BCL-xL and BCL-W. It also showed effect on lymphoma, small-cell lung cancer carcinoma cell lines, primary patient-derived cells, and in tumor xenografts. However, it cannot be orally administered. Although these inhibitors have shown low IC50 values and good BCL2 binding affinities, one of the disadvantages of these inhibitors is that they are pan active. Platelets require BCL-xL for their survival. Hence such pan active agents will affect the platelet count of the body. Owing to high degree of homology between BCL2 family of anti-apoptotic proteins, it is challenging to design molecules that specifically inhibit any one among them.

Fig. 2. Schematic showing various strategies to target BCL2. (G. Radha, Cancer. 2017).

References:

  1. Cui J, Placzek WJ. Post-Transcriptional Regulation of Anti-Apoptotic BCL2 Family Members. International Journal of Molecular Sciences. 2018;19(1):308.
  2. GudapureddyRadhaSathees C.Raghavan. BCL2: A promising cancer therapeutic target. Biochimica et Biophysica Acta (BBA) Volume 1868, Issue 1, August 2017, Pages 309-314.
  3. Jiang Z, Yu F, Li M. Upregulation of BCL2 19 kD Protein-Interacting Protein 3 (BNIP3) is Predictive of Unfavorable Prognosis in Uveal Melanoma. Med Sci Monit. 2018 Jul 8; 24:4711-4717.
  4. Vogler M. Targeting BCL2-Proteins for the Treatment of Solid Tumours. Adv Med. 2014; 2014:943648. Epub. 2014 Aug 27.