TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer.
TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer.
复制标题
DOI：
10.1038/ncomms5527
复制
发表时间：
2014-07-31
影响因子：
16.6
通讯作者：
D'Silva, Nisha J.
中科院分区：
文献类型：
--
作者：
Banerjee, Rajat;Russo, Nickole;Liu, Min;Basrur, Venkatesha;Bellile, Emily;Palanisamy, Nallasivam;Scanlon, Christina S.;van Tubergen, Elizabeth;Inglehart, Ronald C.;Metwally, Tarek;Mani, Ram-Shankar;Yocum, Anastasia;Nyati, Mukesh K.;Castilho, Rogerio M.;Varambally, Sooryanarayana;Chinnaiyan, Arul M.;D'Silva, Nisha J.
头颈部癌（SCCHN）是一种常见的、侵袭性的、难治性的癌症，具有高复发率和死亡率，但难治性的机制仍不清楚。在这里，我们描述了AAA-ATP酶TRIP 13促进治疗抗性的机制。TRIP 13在非恶性细胞中的过表达导致恶性转化。TRIP 13在SCCHN中的高表达导致侵袭性、治疗抗性肿瘤和增强的DNA损伤修复。使用质谱，我们确定介导非同源末端连接（NHEJ）的DNA-PKcs复合物蛋白，作为TRIP 13结合伴侣。使用修复缺陷报告系统，我们表明，TRIP 13促进NHEJ，即使同源重组是完整的。重要的是，TRIP 13的过表达使SCCHN对DNA-PKcs的抑制剂敏感。因此，这项研究定义了SCCHN中治疗耐药性的新机制，并强调了靶向NHEJ以克服SCCHN和可能过度表达TRIP 13的其他癌症治疗失败的重要性。
Head and neck cancer (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment-resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment-resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate non homologous end joining (NHEJ), as TRIP13 binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.
登录
查看更多内容
影响因子：
48
作者：
Fischbach, Claudia;Chen, Ruth;Mooney, David J.
通讯作者：
Mooney, David J.
影响因子：
8
作者：
Eymin, B;Leduc, C;Gazzeri, S
通讯作者：
Gazzeri, S
DOI：
10.1002/hed.21198
发表时间：
2010-04
影响因子：
2.9
作者：
Brenner, J. Chad;Graham, Martin P.;Kumar, Bhavna;Saunders, Lindsay M.;Kupfer, Robbi;Lyons, Robert H.;Bradford, Carol R.;Carey, Thomas E.
通讯作者：
Carey, Thomas E.
影响因子：
16
作者：
Adamo, Adele;Collis, Spencer J.;La Volpe, Adriana
通讯作者：
La Volpe, Adriana
影响因子：
11.2
作者：
Ginos, MA;Page, GP;Gaffney, PM
通讯作者：
Gaffney, PM