Depletion of BIS sensitizes A549 cells to treatment with cisplatin
Depletion of BIS sensitizes A549 cells to treatment with cisplatin
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DOI：
10.1007/s13273-016-0009-y
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发表时间：
2016-03-31
影响因子：
1.7
通讯作者：
Lee, Jeong-Hwa
中科院分区：
文献类型：
--
作者：
Cui, Mei Nu;Yun, Hye-Hyeon;Lee, Jeong-Hwa
据报道，Bcl-2 相互作用细胞死亡抑制蛋白 (BIS) 是一种抗应激和抗凋亡蛋白，在多种癌症中高水平表达。在之前的一项研究中，我们报道了非小细胞肺癌组织中 BIS 的高水平表达。为了探讨这一发现在肺癌中的意义，在本研究中，我们研究了 BIS 消耗对抗肿瘤药物治疗后 A549 细胞存活的影响。 BIS 敲除由 CRISPR/Cas9 系统制备的 A549 细胞，显示顺铂治疗的存活率大幅下降。 Western blotting 和定量实时 PCR 分析表明，在抗凋亡 Bcl-2 家族蛋白中，Mcl-1 的表达因 BIS 的缺失而降低，是在蛋白水平而非 mRNA 水平。由于 BIS 表达已被证明受 HSF1 调节，我们随后说明了 HSF1 抑制剂 KRIBB11 对顺铂诱导的 A549 细胞毒性的敏化作用，并伴随着 BIS 和 Mcl-1 表达的减少。我们的结果表明，BIS 介导的 Mcl-1 稳定化代表了癌症治疗的潜在治疗靶点。
Bcl-2 interacting cell death suppressor (BIS), an anti-stress and ant-apoptotic protein, has been reported to be expressed at high levels in various cancers. In a previous study, we reported on a high level of expression of BIS in non small cell lung cancer tissues. To explore the significance this finding in lung cancer, in this study, we investigated the effect of BIS depletion on the survival of A549 cells upon treatment with anti-tumor agents. BIS knock out A549 cells, prepared by the CRISPR/Cas9 system, revealed a substantial decrease in survival to cisplatin treatment. Western blotting and quantitative real time PCR assays indicated that, among the anti-apoptotic Bcl-2 family proteins, the expression of Mcl-1 was decreased by BIS depletion at the protein level not at the mRNA level. Since BIS expression has been shown to be regulated by HSF1, we subsequently illustrated the sensitization effect of KRIBB11, a HSF1 inhibitor, on cisplatin-induced toxicity in A549 cells, accompanied by a decrease in both BIS and Mcl-1 expression. Our results suggest that BIS-mediated Mcl-1 stabilization represents a potential therapeutic target for cancer therapy.