Fanconi Anemia pathway heterogeneity revealed by cisplatin and oxaliplatin treatments
Fanconi Anemia pathway heterogeneity revealed by cisplatin and oxaliplatin treatments
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DOI：
10.1016/j.canlet.2009.11.009
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发表时间：
2010-06-01
期刊：
影响因子：
9.7
通讯作者：
Willers, Henning
中科院分区：
文献类型：
--
作者：
Kachnic, Lisa A.;Li, Li;Willers, Henning
范可尼贫血（FA）蛋白形成的途径的遗传或表观遗传失活发生在几种癌症类型中，包括头颈部鳞状细胞癌（HNSCC），使受影响的肿瘤对DNA交联剂潜在地超敏感。然而，其他常用癌症治疗剂在FA通路缺陷细胞中的细胞毒性仍有待确定。在这里，我们重点研究了顺铂和奥沙利铂在一组HNSCC和成纤维细胞系中的作用。我们发现FANCC和FANCD 2突变细胞对铂类药物的敏感性出乎意料地高于FANCA突变细胞，并且由FANCA和FANCC介导的FANCD 2的单泛素化对于铂类药物耐药不是必需的。有趣的是，铂超敏反应可以从丝裂霉素C超敏反应中分离出来，提示不同的潜在机制。FANCD 2或RAD 51亚核灶不能作为FANCC/FANCD 2突变细胞铂超敏反应的生物标志物。我们的数据增加了一个新兴的证据表明，FA途径不是线性的，存在几个具有不同功能的蛋白质亚复合物。建立生物标志物来预测具有特异性FA缺陷的肿瘤对化疗药物的敏感性将是重要的。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents. However, the cytotoxicity of other commonly used cancer therapeutics in cells with FA pathway defects remains to be defined. Here, we focused on the effects of cisplatin and oxaliplatin in a panel of HNSCC and fibroblast cell lines. We found that FANCC- and FANCD2-mutant cells were unexpectedly more sensitive to platinum drugs than FANCA-mutant cells, and mono-ubiquitination of FANCD2, which is mediated by the FANCA and FANCC containing FA core complex was not required for platinum resistance. Interestingly, platinum hypersensitivity could be dissociated from mitomycin C hypersensitivity suggesting different underlying mechanisms. FANCD2 or RAD51 subnuclear foci were not useful as biomarkers of platinum hypersensitivity of FANCC/FANCD2-mutant cells. Our data add to an emerging body of evidence indicating that the FA pathway is not linear and that several protein subcomplexes with different functions exist. It will be important to establish biomarkers that can predict the sensitivity of tumors with specific FA defects to chemotherapeutic agents. (C) 2009 Elsevier Ireland Ltd. All rights reserved.