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Review
. 2018 May;8(5):180002.
doi: 10.1098/rsob.180002.

Targeting BCL-2 regulated apoptosis in cancer

Kirsteen J Campbell  1   2 , Stephen W G Tait  3   2
Affiliations
Review

Targeting BCL-2 regulated apoptosis in cancer

Kirsteen J Campbell et al. Open Biol. 2018 May.

Abstract

The ability of a cell to undergo mitochondrial apoptosis is governed by pro- and anti-apoptotic members of the BCL-2 protein family. The equilibrium of pro- versus anti-apoptotic BCL-2 proteins ensures appropriate regulation of programmed cell death during development and maintains organismal health. When unbalanced, the BCL-2 family can act as a barrier to apoptosis and facilitate tumour development and resistance to cancer therapy. Here we discuss the BCL-2 family, their deregulation in cancer and recent pharmaceutical developments to target specific members of this family as cancer therapy.

Keywords: BAX/BAK; BCL-2 family; apoptosis.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
The BCL-2 family is composed of pro-survival and pro-apoptotic proteins. BCL-2 family members show sequence homology to BCL-2 in one or more BH (BCL-2 homology) domain. These proteins can be divided into pro-survival and pro-apoptotic proteins. Within the pro-apoptotic members there is a further subdivision between the multi-BH domain containing effector proteins and those proteins whose only region of homology to BCL-2 is BH3 (known as BH3-only proteins). Membrane insertion is mediated by transmembrane domains (TMD) present in pro-survival, effector and some BH3-only proteins (*BIM, BIK and HRK).
Figure 2.
Figure 2.
BCL-2 family interactions regulate mitochondrial outer membrane permeabilization (MOMP). Interaction between pro-survival and pro-apoptotic BCL-2 proteins sets a threshold for activation of apoptosis. BCL-2-like pro-survival proteins inhibit BAX/BAK activation whereas BH3-only proteins promote BAX/BAK oligomerization. Drugs mimicking the action of BH3-only proteins indirectly lead to BAX/BAK activation. This allows MOMP, apoptosome formation and subsequent caspase activation and apoptosis.
Figure 3.
Figure 3.
Specific interactions of BH3-only with pro-survival proteins. Some BH3-only proteins (BIM, PUMA and BID) are promiscuous and can bind all pro-survival BCL-2 proteins, whereas others (BAD and NOXA) show a more restricted binding pattern.
Figure 4.
Figure 4.
Frequency of genomic alteration of pro-survival BCL-2 proteins in cancer. Frequency of amplification (circle), mutation (triangle) or deletion (square) of pro-survival BCL-2 members in a range of cancers. Data mined from TCGA studies through cBioportal [77]. BCL-2 (black), BCL-XL (BCL2L1 blue), MCL-1 (red), BFL (BCL2A1 grey), BCL-W (BCL2L2 purple). AML, acute myeloid leukaemia [78], 173 cases. Bladder, urothelial carcinoma nature (TCGA provisional), 408 cases. Breast, invasive carcinoma (TCGA provisional), 1100 cases. GBM, glioblastoma [79], 166 cases. HNSCC, head and neck squamous cell carcinoma (TCGA provisional), 522 cases. ccRCC, kidney renal clear cell carcinoma [80], 534 cases. Lung adenocarcinoma (TCGA provisional), 517 cases. Thyroid, papillary thyroid carcinoma [81], 509 cases. Stomach adenocarcinoma (TCGA provisional), 415 cases. Uterine, corpus endometrial carcinoma [82], 177 cases.
Figure 5.
Figure 5.
Selectivity of BH3-mimetic drugs under clinical investigation. Drugs specifically targeting BCL-2 (Venetoclax/ABT-199), BCL-2, BCL-XL and BCL-W (Navitoclax/ABT263) or MCL-1 (AMG176, S64315/MIK665) are now in clinical trial/use.
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