Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia.
Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia.
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BTSA1 直接激活 BAX 克服了急性髓系白血病的细胞凋亡抵抗。
DOI：
10.1016/j.ccell.2017.09.001
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发表时间：
2017-10-09
期刊：
影响因子：
50.3
通讯作者：
Gavathiotis E
中科院分区：
文献类型：
--
作者：
Reyna DE;Garner TP;Lopez A;Kopp F;Choudhary GS;Sridharan A;Narayanagari SR;Mitchell K;Dong B;Bartholdy BA;Walensky LD;Verma A;Steidl U;Gavathiotis E
BCL-2家族蛋白BAX是细胞凋亡的中心介质。抗凋亡BCL-2蛋白的过表达通过抑制BAX及其激活剂而促进肿瘤发展和对治疗的抗性。我们报告了BTSA 1的发现，BTSA 1是一种优化的BAX激活剂，其以高亲和力和特异性与N-末端激活位点结合，并诱导BAX的构象变化，从而导致BAX介导的细胞凋亡。BTSA 1诱导的BAX激活有效地促进白血病细胞系和患者样品中的细胞凋亡，同时保留健康细胞。BAX表达水平和胞质构象调节对BTSA 1的敏感性。BTSA 1有效抑制人类急性髓性白血病（AML）异种移植物，并增加宿主存活率，而无毒性。这项研究提供了直接BAX激活作为AML治疗策略的概念验证。Reyna等人开发了BTSA 1，一种经细胞内优化的BAX激活剂，并表明BTSA 1诱导的BAX激活有效地并选择性地促进急性髓性白血病细胞的凋亡。他们进一步证明BAX表达水平和胞质构象调节对BTSA 1的敏感性。
The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct BAX activation as a treatment strategy in AML. Reyna et al. develop BTSA1, a pharmacologically optimized BAX activator, and show that BTSA1-induced BAX activation effectively and selectively promotes apoptosis of acute myeloid leukemia cells. They further demonstrate that the BAX expression level and cytosolic conformation regulate the sensitivity to BTSA1.
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