Essential role for Bim in mediating the apoptotic and antitumor activities of immunotoxins
Essential role for Bim in mediating the apoptotic and antitumor activities of immunotoxins
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DOI：
10.1038/onc.2017.111
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发表时间：
2017-08-31
期刊：
影响因子：
8
通讯作者：
FitzGerald, D. J.
中科院分区：
文献类型：
--
作者：
Antignani, A.;Segal, D.;FitzGerald, D. J.
蛋白质合成对调节细胞动态平衡至关重要，当不受限制时，它可以导致肿瘤的发生。来自假单胞菌外毒素的免疫毒素是抗体-毒素融合蛋白，通过真核细胞延伸因子-2的ADP-核糖化作用抑制哺乳动物细胞的蛋白质合成。在这里，我们研究了Bcl-2家族蛋白在癌细胞对免疫毒素攻击的反应中的作用。除了众所周知的在蛋白质合成受到抑制后存活的Bcl-2家族成员Mcl-1的减少外，我们首次表明免疫毒素也降低了选定的促凋亡BH-3蛋白的水平。其中，只有Bim蛋白水平与免疫毒素诱导凋亡反应的能力相关。为了支持我们的发现，我们验证了Bim基因敲除完全消除了免疫毒素介导的细胞凋亡。此外，携带野生型或BID基因敲除肿瘤的小鼠对免疫毒素治疗的反应是生长动力学下降，而移植了Bim基因敲除肿瘤的小鼠在免疫毒素治疗后肿瘤大小没有缩小或生存时间没有延长。根据这些结果，我们得出结论，BIM的表达是肿瘤细胞死亡的主要易感因素，因此，构成了一个潜在的生物标记物，可以在免疫毒素治疗之前进行评估。为了支持这一假设，临床上，我们在免疫毒素治疗前分析了患者细胞，并报告说，与表达低水平Bim的样本相比，高水平Bim蛋白的毛细胞白血病样本的白血病细胞计数下降幅度更大。
Protein synthesis is crucial for regulating cell homeostasis and, when unrestricted, it can lead to tumorigenesis. Immunotoxins derived from Pseudomonas exotoxin are antibody-toxin fusion proteins that inhibit protein synthesis of mammalian cells via ADP-ribosylation of the eukaryotic elongation factor-2. Here we investigate the role of the Bcl-2 family proteins in the response of cancer cells to immunotoxin challenge. Besides the well-known reduction of the prosurvival Bcl-2 family member, Mcl-1, following inhibition of protein synthesis, we show for the first time that immunotoxins also reduce the levels of selected proapoptotic BH-3-only proteins. Among these, only Bim protein levels correlated with the ability of immunotoxins to induce an apoptotic response. To support our findings, we verified that a Bim knockout completely abolished immunotoxin-mediated apoptosis. Further, mice bearing either wild-type or Bid knockout tumors responded to immunotoxin treatment with a decrease in growth kinetics, whereas mice engrafted with Bim knockout tumors showed no reduction in tumor size or prolongation of survival following immunotoxin treatment. From these results, we conclude that Bim expression is a major susceptibility factor for tumor cell death and, as such, constitutes a potential biomarker that could be evaluated before immunotoxin treatment. In support of this hypothesis, clinically, we analyzed patient cells before immunotoxin treatment and report that samples of hairy cell leukemia with high levels of Bim protein responded with a greater decrease in leukemic cell count compared with those samples expressing a low level of Bim.