RIP1 expression is necessary for CD30-mediated cell death induction in anaplastic large-cell lymphoma cells
RIP1 expression is necessary for CD30-mediated cell death induction in anaplastic large-cell lymphoma cells
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DOI：
10.1038/labinvest.2013.50
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发表时间：
2013-04
影响因子：
5
通讯作者：
B. Hirsch;E. V. D. Wall;M. Hummel;H. Dürkop
中科院分区：
文献类型：
--
作者：
B. Hirsch;E. V. D. Wall;M. Hummel;H. Dürkop
CD30是肿瘤坏死因子受体(TNFR)超家族成员之一，在间变性大细胞淋巴瘤(ALCL)的肿瘤细胞中持续表达。在典型的核因子κB抑制或蛋白酶体抑制的情况下，CD30刺激诱导大量caspase依赖的细胞死亡。然而，CD30是一个缺乏死亡结构域(DD)的TNFR，它不能招募含有Tradd(TNFR1相关DD蛋白)或FADD(Fas相关DD结构域蛋白)与受体相互作用蛋白1(RIP1)和caspase-8的死亡诱导复合体。因此，CD30诱导淋巴细胞细胞死亡的机制仍不清楚。在这里，我们证明了siRNA阻断RIP1或Necrostatin-1药物抑制RIP1几乎完全阻止了CD30诱导的细胞死亡。此外，在激光共聚焦扫描显微镜下，我们发现CD30诱导的RIP1积聚在NFκB抑制的ALCL细胞的细胞膜上。最后，根据免疫组织学显示的RIP1的存在与否，原发ALCL病例可细分为两组。综上所述，我们的研究确定RIP1是CD30诱导的细胞死亡的关键介质，具有凋亡和坏死性下垂的特征。CD30抗体与κB/蛋白酶体抑制剂联合应用可能导致CD30诱导的细胞死亡。
CD30, a member of the tumor necrosis factor receptor (TNFR) superfamily, is consistently expressed by tumor cells of anaplastic large-cell lymphoma (ALCL). CD30 stimulation induces massive caspase-dependent cell death of ALCL cells in case of canonical NFκB inhibition or proteasome inhibition. However, CD30, a TNFR lacking a death domain (DD), is unable to recruit a death inducing complex containing TRADD (TNFR1-associated DD-protein) or FADD (FAS-associated DD-domain protein) together with the receptor-interacting protein 1 (RIP1) and caspase-8. Thus, the mechanism explaining CD30-induced cell death of lymphocytes remains obscure. Here, we demonstrate that blockage of RIP1 by siRNA or pharmacological inhibition of RIP1 by Necrostatin-1 almost completely prevented CD30-induced cell death. In addition, we revealed CD30-induced accumulation of RIP1 at the cytoplasma membrane of NFκB-inhibited ALCL cells by confocal laser scanning microscopy. Finally, primary ALCL cases can be subdivided into two groups based on the presence or absence of RIP1 as revealed by immunohistology. Taken together, our study identified RIP1 as a crucial mediator of CD30-induced cell death that bears features of apoptosis as well as necroptosis. RIP1 expression in ALCL tumor cells might eligible for the therapeutic application of CD30 antibodies in combination with NFκB/proteasome inhibitors that should result in CD30-induced cell death.