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Bcl-2 overexpression Inhibits TRAIL-induced Apoptosis in Type II Cells

机译:Bcl-2过表达抑制II型细胞中的血迹诱导的细胞凋亡

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Resistance to current treatment protocols remains a major concern in clinical oncology and may be caused by defects in apoptosis programs. Here we report that overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma or breast carcinoma cell lines. Bcl-2 overexpression reduced TRAIL-induced cleavage of caspase-8 and Bid and blocked cleavage of caspase-9, -7 and -3 into active subunits and cleavage of the caspase substrates DFF45 or PARP. In contrast, in SKW lymphoblastoid cells, TRAIL-induced activation of caspase-8 directly translated into full activation of caspases and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mito-chondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types. By demonstrating a cell type dependent regulation of the TRAIL signaling pathway, these findings may have important clinical implication. Thus, strategies targeting the molecular basis of resistance towards TRAIL may be necessary in some tumors for cancer therapy with TRAIL.
机译:对当前治疗方案的抗性仍然是临床肿瘤学中的主要问题,并且可能是由凋亡方案中的缺陷引起的。在这里,我们举报了BCL-2的过度表达赋予了神经母细胞瘤,胶质母细胞瘤或乳腺癌细胞系的痕迹保护。 BCL-2过表达降低了胱天蛋白酶-8的诱导的Trail诱导的裂解切割,并将Caspase-9,-7和-3的BID和封闭的裂解成活性亚基和胱天蛋白酶基材DFF45或PARP的切割。相比之下,在SKW淋巴细胞细胞中,Caspase-8的Trail诱导激活直接转化为完全活化的胱天蛋白酶和凋亡,虽然Bcl-2同样抑制了Mito膜膜的损失和细胞色素的释放丧失C,AIF和SMAC在所有细胞类型中的线粒体。通过展示TRAIL信号通路的细胞类型依赖性调节,这些发现可能具有重要的临床意义。因此,在癌症治疗的一些肿瘤中可能需要靶向对迹线的抗性的分子基础的策略。

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