Abstract
BCL-2 family proteins are central regulators of apoptosis and represent prime therapeutic targets for overcoming cell death resistance in malignancies. However, plasticity of anti-apoptotic members, such as MCL-1, often allows for a switch in cell death dependency patterns that lie outside the binding profile of targeted BH3-mimetics. Therefore discovery of therapeutics that effectively inactivate all anti-apoptotic members is a high priority. To address this we tested the potency of a hydrocarbon stapled BIM BH3 peptide (BIM SAHBA) to overcome both BCL-2 and MCL-1 apoptotic resistance given BIM’s naturally wide ranging affinity for all BCL-2 family multidomain members. BIM SAHBA effectively killed diffuse large B-cell lymphoma (DLBCL) cell lines regardless of their anti-apoptotic dependence. Despite BIM BH3’s ability to bind all BCL-2 anti-apoptotic proteins, BIM SAHBA’s dominant intracellular target was MCL-1 and this specificity was exploited in sequenced combination BH3-mimetic treatments targeting BCL-2, BCL-XL, and BCL-W. Extending this MCL-1 functional dependence, mouse embryonic fibroblasts (MEFs) deficient in MCL-1 were resistant to mitochondrial changes induced by BIM SAHBA. This study demonstrates the importance of understanding BH3 mimetic functional intracellular affinities for optimized use and highlights the diagnostic and therapeutic promise of a BIM BH3 peptide mimetic as a potential MCL-1 inhibitor.
Highlights
The BCL-2 family can be divided into multidomain anti-apoptotic (e.g. BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1) and pro-apoptotic (e.g. BAK, BAX) proteins
A panel of 18 human diffuse large B-cell lymphoma (DLBCL) cell lines was treated with increasing concentrations of BIM SAHBA, ABT-737, and ABT-199 to determine cell death as a result of distinctive anti-apoptotic targeting (Figure 1 and Supplementary Figure 1A)
No death was measured in any cell line treated with a hydrocarbon-stapled BH3 point mutant control (BIM SAHBA (R153D)) or vehicle alone indicating BIM-BH3 sequence-specific cell death induction (Supplementary Figure 1B and 1C) [16, 17, 19]
Summary
The BCL-2 family can be divided into multidomain anti-apoptotic (e.g. BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1) and pro-apoptotic (e.g. BAK, BAX) proteins. The functional interactions between these anti- and pro-apoptotic partners is controlled by a third group of proteins known as BH3-only proteins (e.g. BIM, BID, PUMA, BIK, BAD, NOXA, BMF) which contain one of four conserved BCL-2 homology (BH) domains. Cancer cells have long been known to evade cell death through overexpression of anti-apoptotic BCL-2 members or through down-regulation of BH3-only proteins [1]. To overcome these hurdles there is a great pharmacologic crusade to develop agents that directly engage BCL-2 family proteins to induce death regardless of the cell’s origin or genetic perturbations [2]. Many BH3-mimetics, have not effectively translated to the clinic or have been proven to work, at least in part, independent of the BCL-2 network [3,4,5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
