Association of caspase-8 mutation with chemoresistance to cisplatin in HOC313 head and neck squamous cell carcinoma cells
Association of caspase-8 mutation with chemoresistance to cisplatin in HOC313 head and neck squamous cell carcinoma cells
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DOI：
10.1016/j.bbrc.2009.10.090
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发表时间：
2009-12-18
影响因子：
3.1
通讯作者：
Ikeda, Masa-Aki
中科院分区：
文献类型：
--
作者：
Liu, Juan;Uematsu, Hiroshi;Ikeda, Masa-Aki
Caspase-8是死亡受体途径中重要的上游细胞凋亡调节因子。然而，在携带p53突变的头颈部鳞状细胞癌中，caspase-8突变与化疗敏感性的关系尚不清楚。在这项研究中，我们在一个耐药的HOC313 HNSCC细胞系中发现了一个caspase-8无义突变，伴随着第二个等位基因的丢失。无义突变(R68X)导致所有已定义功能结构域的截断。通过稳定转染野生型caspase-8来重建caspase-8可使细胞对顺铂敏感，但不能诱导足叶乙甙诱导的细胞凋亡。与此一致的是，顺铂而不是依托泊苷在caspase-8重组的HOC313细胞中诱导了肿瘤坏死因子-α和TRAIL的mRNA，并伴随着重组的caspase-8及其下游的caspase-3的激活。这些结果表明，caspase-8的缺失在HOC313细胞获得顺铂耐药的过程中起重要作用。(C)2009 Elsevier Inc.保留所有权利。
Caspase-8 is a critical upstream mediator of apoptosis in the death receptor pathway. However, the relationship between caspase-8 mutation and chemosensitivity remain unclear in head and neck squamous cell carcinoma (HNSCC) carrying p53 mutation. In this study, we identified a caspase-8 nonsense mutation, accompanied by the loss of the second allele, in a drug-resistant HOC313 HNSCC cell line. The nonsense mutation (R68X) leads to truncation of all defined functional domains. Reconstitution of caspase-8 by stable transfection of wild-type caspase-8 sensitized the cells to cisplatin-, but not etoposide-induced apoptosis. Consistent with this, cisplatin, but not etoposide, induced TNF-alpha and TRAIL mRNA in caspase-8 reconstituted HOC313 cells, accompanied by activation of the reconstituted caspase-8 and its downstream caspase-3. These results indicate that the loss of caspase-8 plays an important role in acquisition of chemoresistance to cisplatin in HOC313 cells. (C) 2009 Elsevier Inc. All rights reserved.