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首页> 外文期刊>Oncogene >Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway
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Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

机译：三氧化砷通过BCL-2控制的途径诱导受调节的死亡受体无关的细胞死亡

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Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As2O3 induces cell death in a caspase-2- and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As2O3-induced cell death. In detail, we demonstrate that As2O3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As2O3-induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETD-fmk. Nevertheless, As2O3-induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As2O3-induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As2O3-induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.
机译：砷三氧化砷（As2O3，亚砷酸盐）有效地杀死各种血液学恶性肿瘤的细胞，并成功地用于治疗急性暴露细胞白血病。在那里和在淋巴细胞中，我们证明AS2O3以Caspase-2-和-9-underys的方式诱导细胞死亡。在这里，我们通过AS2O3诱导的细胞死亡中的FADD / CASPASE-8死亡诱导信号综合体来解决死亡受体信号传导的潜在作用。详细地，我们证明As2O3独立于Caspase-8或FADD诱导细胞死亡，并且不能被CD95 / Fas受体配体相互作用的破坏阻塞。与死亡受体结扎诱导的细胞凋亡不同，AS2O3诱导的细胞死亡未被广谱胱天蛋白酶抑制剂Z-VAD-FMK或Caspase-8特异性抑制剂Z-IETD-FMK阻断。然而，AS2O3诱导的细胞死亡以规定的方式发生，并且在BCL-2过表达时脱落。相比之下，As2O3诱导的细胞消除既不被Caspase-9抑制剂Z-Lehd-FMK阻断，也不通过显性阴性胱天蛋白酶-9突变体的表达基本上抑制。我们的数据总共表明，AS2O3诱导的细胞死亡是独立于细胞凋亡的外在死亡受体途径发生的。细胞死亡完全通过内在的Bcl-2控制的线粒体途径进行，但是，不依赖于Caspase-9。

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