Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells

Molecular Cancer

Research

Yi-Wen Huang¹  Qi-En Wang²  Chunhua Han²  Gulzar Wani²  Keisha Milum²  Altaf A Wani³  Jürgen Thomale⁴ 

[1] Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, OH, USA;Department of Radiology, The Ohio State University, 43210, Columbus, OH, USA;Department of Radiology, The Ohio State University, 43210, Columbus, OH, USA;Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, OH, USA;Department of Molecular and Cellular Biochemistry, The Ohio State University, 43210, Columbus, OH, USA;DNA Research Chair, King Saud University, Riyadh, Saudi Arabia;Institut für Zellbiolgoie, Universitätsklinikum Essen, Germany;

关键词: CDDP;    Nucleotide Excision Repair;    Ovarian Cancer Cell Line;    Homologous Recombination Repair;    Nucleotide Excision Repair Pathway;   

DOI  :  10.1186/1476-4598-10-24

 received in 2011-01-03, accepted in 2011-03-08,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundWhile platinum-based chemotherapeutic agents are widely used to treat various solid tumors, the acquired platinum resistance is a major impediment in their successful treatment. Since enhanced DNA repair capacity is a major factor in conferring cisplatin resistance, targeting of DNA repair pathways is an effective stratagem for overcoming cisplatin resistance. This study was designed to delineate the role of nucleotide excision repair (NER), the principal mechanism for the removal of cisplatin-induced DNA intrastrand crosslinks, in cisplatin resistance and reveal the impact of DNA repair interference on cisplatin sensitivity in human ovarian cancer cells.ResultsWe assessed the inherent NER efficiency of multiple matched pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines and their expression of NER-related factors at mRNA and protein levels. Our results showed that only the cisplatin-resistant ovarian cancer cell line PEO4 possessed an increased NER capacity compared to its inherently NER-inefficient parental line PEO1. Several other cisplatin-resistant cell lines, including CP70, CDDP and 2008C13, exhibited a normal and parental cell-comparable NER capacity for removing cisplatin-induced DNA intrastrand cross-links (Pt-GG). Concomitant gene expression analysis revealed discordance in mRNA and protein levels of NER factors in various ovarian cancer cell lines and NER proteins level were unrelated to the cisplatin sensitivity of these cell lines. Although knockdown of NER factors was able to compromise the NER efficiency, it only caused a minimal effect on cisplatin sensitivity. On the contrary, downregulation of BRCA2, a critical protein for homologous recombination repair (HRR), significantly enhanced the efficacy of cisplatin in killing ovarian cancer cell line PEO4.ConclusionOur studies indicate that the level of NER factors in ovarian cancer cell lines is neither a determinant of their NER capacity nor of the sensitivity to cisplatin, and suggest that manipulation of the HRR but not the NER factor expression provides an effective strategy for sensitizing cisplatin-resistant tumors to platinating agents.

【 授权许可】

CC BY   
© Wang et al; licensee BioMed Central Ltd. 2011