Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression

Molecular Cancer

Research

Jürgen Thomale¹  Astrid Schneider²  Andrea Piée-Staffa³  Bernd Kaina³  Beate Köberle³  Ulrike Sied³  Svetlana Usanova³ 

[1] Institute for Cell Biology, University of Duisburg-Essen Medical School, Hufeland Strasse 55, 45122, Essen, Germany;Institute of Medical Biostatistics, Epidemiology and Informatics, Clinical Centre of University of Mainz, Germany, Obere Zahlbacher Strasse 69, 55131, Mainz, Germany;Institute of Toxicology, Clinical Centre of University of Mainz, Obere Zahlbacher Strasse 67, 55131, Mainz, Germany;

关键词: Nucleotide Excision Repair;    Bladder Cancer Cell;    Testicular Germ Cell Tumour;    Tail Moment;    Interstrand Crosslinking;   

DOI  :  10.1186/1476-4598-9-248

 received in 2010-05-11, accepted in 2010-09-16,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCisplatin based chemotherapy cures over 80% of metastatic testicular germ cell tumours (TGCT). In contrast, almost all other solid cancers in adults are incurable once they have spread beyond the primary site. Cell lines derived from TGCTs are hypersensitive to cisplatin reflecting the clinical response. Earlier findings suggested that a reduced repair capacity might contribute to the cisplatin hypersensitivity of testis tumour cells (TTC), but the critical DNA damage has not been defined. This study was aimed at investigating the formation and repair of intrastrand and interstrand crosslinks (ICLs) induced by cisplatin in TTC and their contribution to TTC hypersensitivity.ResultsWe observed that repair of intrastrand crosslinks is similar in cisplatin sensitive TTC and resistant bladder cancer cells, whereas repair of ICLs was significantly reduced in TTC. γH2AX formation, which serves as a marker of DNA breaks formed in response to ICLs, persisted in cisplatin-treated TTC and correlated with sustained phosphorylation of Chk2 and enhanced PARP-1 cleavage. Expression of the nucleotide excision repair factor ERCC1-XPF, which is implicated in the processing of ICLs, is reduced in TTC. To analyse the causal role of ERCC1-XPF for ICL repair and cisplatin sensitivity, we over-expressed ERCC1-XPF in TTC by transient transfection. Over-expression increased ICL repair and rendered TTC more resistant to cisplatin, which suggests that ERCC1-XPF is rate-limiting for repair of ICLs resulting in the observed cisplatin hypersensitivity of TTC.ConclusionOur data indicate for the first time that the exceptional sensitivity of TTC and, therefore, very likely the curability of TGCT rests on their limited ICL repair due to low level of expression of ERCC1-XPF.

【 授权许可】

Unknown   
© Usanova et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.