RAD51 and BRCA2 Enhance Oncolytic Adenovirus Type 5 Activity in Ovarian Cancer

被引：16

作者：

Tookman, Laura A. ^{[1
]}

Browne, Ashley K. ^{[1
]}

Connell, Claire M. ^{[1
]}

Bridge, Gemma ^{[1
]}

Ingemarsdotter, Carin K. ^{[1
]}

Dowson, Suzanne ^{[2
]}

Shibata, Atsushi ^{[3
]}

Lockley, Michelle ^{[1
]}

Martin, Sarah A. ^{[1
]}

McNeish, Iain A. ^{[1
,2
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England

[2] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[3] Gunma Univ, Adv Sci Res Leaders Dev, Maebashi, Gunma, Japan

来源：

MOLECULAR CANCER RESEARCH | 2016年 / 14卷 / 01期

基金：

英国医学研究理事会;

关键词：

STRAND BREAK REPAIR; MRE11; COMPLEX; MRE11-RAD50-NBS1; DNA-DAMAGE; E4; 34K; PROTEIN; DELETION; MUTANT; BIOLUMINESCENCE; DEGRADATION;

D O I：

10.1158/1541-7786.MCR-15-0188-T

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Homologous recombination (HR) function is critically important in high-grade serous ovarian cancer (HGSOC). HGSOC with intact HR has a worse prognosis and is less likely to respond to platinum chemotherapy and PARP inhibitors. Oncolytic adenovirus, a novel therapy for human malignancies, stimulates a potent DNA damage response that influences overall antitumor activity. Here, the importance of HR was investigated by determining the efficacy of adenovirus type 5 (Ad5) vectors in ovarian cancer. Using matched BRCA2-mutant and wild-type HGSOC cells, it was demonstrated that intact HR function promotes viral DNA replication and augments overall efficacy, without influencing viral DNA processing. These data were confirmed in a wider panel of HR competent and defective ovarian cancer lines. Mechanistically, both BRCA2 and RAD51 localize to viral replication centers within the infected cell nucleus and that RAD51 localization occurs independently of BRCA2. In addition, a direct interaction was identified between RAD51 and adenovirus E2 DNA binding protein. Finally, using functional assays of HR competence, despite inducing degradation of MRE11, Ad5 infection does not alter cellular ability to repair DNA double-strand break damage via HR. These data reveal that Ad5 redistributes critical HR components to viral replication centers and enhances cytotoxicity. (C)2015 AACR.

引用

页码：44 / 55

页数：12

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