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首页> 外文期刊>Apoptosis >Role of Bim in apoptosis induced in H460 lung tumor cells by the spindle poison Combretastatin-A4
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Role of Bim in apoptosis induced in H460 lung tumor cells by the spindle poison Combretastatin-A4

机译：Bim在纺锤体中毒Combretastatin-A4诱导的H460肺肿瘤细胞凋亡中的作用

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摘要

The BH3-only Bcl-2 subfamily member Bim is a well known apoptosis promoting protein. However, the mechanisms upstream of mitochondrion membrane permeability by which Bim is involved in apoptosis have been poorly investigated, particularly in response to agents capable of interfering with the cytoskeleton architecture and arresting cells in mitosis. Based on the observation that Bim is sequestered on the microtubule-array by interaction with the light chain of dynein, we have investigated upon depolymerisation, whether Bim could be involved in the commitment of apoptosis. With this purpose H460 Non Small Lung Cancer Cells (NSLC) were treated with the microtubule damaging agent combretastatin-A4 (CA-4) (7.5 nM; 8–48 h), and various parameters were investigated. Upon treatment, cells arrested in mitosis and died through a caspase-3-dependent mitotic catastrophe. Transient knock down of Bim drastically reduced apoptosis, indicating that this protein was involved in cell death as induced by microtubules disorganisation. In response to increasing conditions of microtubules depolymerisation, we found that the protein level of Bim was strongly upregulated in a time-dependent manner at transcriptional level. Furthermore, Bim was released from microtubule-associated components. Bim was translocated to mitochondria, even in a condition of protein synthesis inhibition, where it showed a markedly increased interaction with Bcl-2. In turn, the fraction of Bax bound to Bcl-2 decreases in response to treatment, thereby indicating that Bim possibly promotes Bax release from the pro-survival protein Bcl-2. Overall, we demonstrated that Bim is required for the CA-4-induced cell death in the H460 lung cancer cell line via activation of the mitochondrial signalling pathway. Defining the contribution of Bim to the mechanism of apoptosis may offer some different clues in view of developing new strategies for chemotherapy with CA-4, underlining the relevance of the cytoskeleton integrity in the apoptotic response.
机译：仅BH3的Bcl-2亚家族成员Bim是众所周知的促凋亡蛋白。然而，Bim参与凋亡的线粒体膜通透性上游机制尚未得到充分研究，特别是对能够干扰细胞骨架结构并将细胞停在有丝分裂中的药物的反应。基于观察到Bim通过与动力蛋白轻链相互作用而被隔离在微管阵列上，我们在解聚后研究了Bim是否可以参与细胞凋亡的发生。为此目的，用微管损伤剂康培他汀-A4（CA-4）（7.5 nM; 8–48 h）处理H460非小细胞肺癌（NSLC），并研究各种参数。治疗后，细胞停在有丝分裂中，并通过caspase-3依赖性有丝分裂灾难而死亡。 Bim的瞬时敲除大大减少了细胞凋亡，表明该蛋白与微管解体诱导的细胞死亡有关。响应于微管解聚条件的增加，我们发现Bim的蛋白水平在转录水平上以时间依赖性方式强烈上调。此外，Bim从与微管相关的成分中释放出来。即使在蛋白质合成抑制的条件下，Bim仍然易位至线粒体，在该条件下，Bim与Bcl-2的相互作用显着增加。继而，响应于治疗，与Bcl-2结合的Bax的分数降低，从而表明Bim可能促进了Bax从存活蛋白Bcl-2的释放。总的来说，我们证明了Bim是通过激活线粒体信号通路在H460肺癌细胞系中CA-4诱导的细胞死亡所必需的。鉴于开发CA-4化疗的新策略，定义Bim对凋亡机制的贡献可能会提供一些不同的线索，强调了细胞骨架完整性与凋亡反应的相关性。

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