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首页> 外文期刊>Cell cycle >Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors
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Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

机译：蛋白Bak和Bax的丢失阻止了组蛋白脱乙酰基酶抑制剂介导的凋亡

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Burkitt lymphoma is characterized by deregulation of c-myc, and therapies targeting c-myc are under investigation as treatments. Histone deacetylase inhibitors are known to abrogate c-myc expression, leading us to examine their effect in a series of Burkitt lymphoma cell lines. While treatment with romidepsin, panobinostat, vorinostat, or belinostat for 48 h resulted in complete cell death in the Ramos and ST486 lines, CA46 and DG75 cells were resistant. In parallel studies, CA46 and DG75 cells were also insensitive to 48 h treatment with the Aurora kinase inhibitors (AKIs) MLN8237 (alisertib), VX-680 (tozasertib), or ZM447439. Bax knockdown is known to lead to HDI resistance, and we found that loss of Bax or both Bak and Bax correlated with resistance to both AKIs and HDIs in the Burkitt cell lines. As proof-of-concept to evaluate the contribution of Bax and Bak to HDI-mediated apoptosis, we found that apoptosis was unaffected in HCT-116 colon carcinoma cells lacking Bak, blunted in cells lacking Bax, and nearly completely abrogated in cells lacking both Bak and Bax compared with wild-type cells. To explore potential clinical variations in Bak and Bax expression, a series of samples from 16 patients diagnosed with Burkitt lymphoma was examined. While the majority of samples were positive for both Bak and Bax, some (3/16) expressed low levels of both proteins. We thus conclude that HDI-mediated and AKI-mediated apoptosis requires mitochondrial engagement, and that baseline Bax and Bak expression may serve as biomarkers for patients with Burkitt lymphoma likely to respond to HDI treatment.
机译：Burkitt淋巴瘤的特征在于c-myc的失调，针对c-myc的疗法正在研究中。已知组蛋白脱乙酰基酶抑制剂可以消除c-myc表达，从而使我们研究其在一系列Burkitt淋巴瘤细胞系中的作用。虽然用罗米地辛，泛比司他，伏立诺他或贝利司他处理48小时导致Ramos和ST486细胞系中的细胞完全死亡，但CA46和DG75细胞具有抗性。在平行研究中，CA46和DG75细胞对Aurora激酶抑制剂（AKI）MLN8237（alisertib），VX-680（tozasertib）或ZM447439处理48小时也不敏感。已知Bax敲低会导致HDI抗性，我们发现Burkitt细胞系中Bax或Bak和Bax的缺失与对AKI和HDI的抗性相关。作为评估Bax和Bak对HDI介导的凋亡的贡献的概念验证，我们发现凋亡在缺乏Bak的HCT-116结肠癌细胞中不受影响，在缺乏Bax的细胞中变钝，而在缺乏Bak的细胞中几乎完全消失Bak和Bax与野生型细胞相比。为了探索Bak和Bax表达的潜在临床差异，检查了16名被诊断患有Burkitt淋巴瘤的患者的一系列样本。虽然大多数样品的Bak和Bax均为阳性，但有些（3/16）样品中两种蛋白的水平都很低。因此，我们得出的结论是，HDI介导的和AKI介导的凋亡需要线粒体参与，并且基线Bax和Bak表达可能充当可能对HDI治疗有反应的Burkitt淋巴瘤患者的生物标志物。

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