Preferential targeting of MCL-1 by a hydrocarbon-stapled BIM BH3 peptide.
Preferential targeting of MCL-1 by a hydrocarbon-stapled BIM BH3 peptide.
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DOI：
10.18632/oncotarget.27262
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发表时间：
2019-10-22
期刊：
影响因子：
--
通讯作者：
LaBelle, James L
中科院分区：
文献类型：
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作者：
Hadji, Abbas;Schmitt, Greta K;LaBelle, James L
BCL-2家族蛋白是细胞凋亡的中心调节因子，是克服恶性肿瘤细胞死亡抵抗的主要治疗靶点。然而，抗凋亡成员（如MCL-1）的可塑性通常允许在靶向bh3模拟物的结合谱之外的细胞死亡依赖模式的切换。因此，发现有效灭活所有抗凋亡成员的治疗方法是当务之急。为了解决这个问题，我们测试了碳氢化合物钉接BIM BH3肽（BIM SAHB a）的有效性，以克服BCL-2和MCL-1的凋亡抗性，因为BIM对所有BCL-2家族多域成员具有天然的广泛亲和力。BIM SAHB A有效杀死弥漫大b细胞淋巴瘤（DLBCL）细胞系，而不考虑其抗凋亡依赖性。尽管BIM BH3能够结合所有BCL-2抗凋亡蛋白，但BIM SAHB A的主要细胞内靶点是MCL-1，这种特异性在针对BCL-2、BCL-XL和BCL-W的序列组合BH3模拟治疗中得到了利用。MCL-1缺失的小鼠胚胎成纤维细胞（mef）对BIM SAHB A诱导的线粒体变化具有抗性，这进一步扩展了MCL-1的功能依赖性。该研究证明了了解BH3模拟功能细胞内亲和力对于优化使用的重要性，并强调了BIM BH3肽模拟物作为潜在MCL-1抑制剂的诊断和治疗前景。
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 SAHB A ) 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 SAHB A 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 SAHB A '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 SAHB A . 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.