Scholz Christian, Richter Antje, Lehmann Mario, Schulze-Osthoff Klaus, Dörken Bernd, Daniel Peter T
Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Buch, Humboldt University, Berlin, Germany.
Oncogene. 2005 Oct 27;24(47):7031-42. doi: 10.1038/sj.onc.1208868.
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.
三氧化二砷（As₂O₃，亚砷酸盐）能有效杀死多种血液系统恶性肿瘤细胞，并已成功应用于急性早幼粒细胞白血病的治疗。在这些细胞以及淋巴细胞中，我们证明As₂O₃以不依赖半胱天冬酶 -2和 -9的方式诱导细胞死亡。在此，我们探讨通过FADD/半胱天冬酶 -8死亡诱导信号复合物的死亡受体信号传导在As₂O₃诱导的细胞死亡中的潜在作用。具体而言，我们证明As₂O₃诱导细胞死亡不依赖于半胱天冬酶 -8或FADD，并且不能通过破坏CD95/Fas受体配体相互作用来阻断。与死亡受体连接诱导的细胞凋亡不同，As₂O₃诱导的细胞死亡不能被广谱半胱天冬酶抑制剂z-VAD-fmk或半胱天冬酶 -8特异性抑制剂z-IETD-fmk阻断。然而，As₂O₃诱导的细胞死亡以一种受调控的方式发生，并且在Bcl-2过表达时被消除。相比之下，As₂O₃诱导的细胞死亡既不能被半胱天冬酶 -9抑制剂z-LEHD-fmk阻断，也不能通过显性负性半胱天冬酶 -9突变体的表达得到显著抑制。我们的数据总体表明，As₂O₃诱导的细胞死亡独立于细胞凋亡的外源性死亡受体途径发生。细胞死亡完全通过内在的、由Bcl-2控制的线粒体途径进行，但该途径不依赖于半胱天冬酶 -9。
