In Vitroandin VivoPotentiation of Radiosensitivity of Malignant Gliomas by Antisense Inhibition of the RAD51 Gene

Ohnishi, Takanori; Taki, Takuyu; Hiraga, Shoju; Arita, Norio; Morita, Takashi

doi:10.1006/bbrc.1998.8440

Cited by 104 publications

(76 citation statements)

References 20 publications

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“…High levels of Rad51 are associated with elevated rates of DNA recombination as well as enhanced resistance to DNA-damaging chemotherapies and/or ionizing radiation in several experimental tumor systems (13 -15). Antisense strategies have been successfully used to attenuate Rad51-mediated radioresistance in in vitro and in vivo studies (16,17). To the best of our knowledge, Rad51 expression, function, or regulation has not been previously studied in STS.…”

Section: Introductionmentioning

confidence: 99%

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

Hannay

Liu

Zhu

et al. 2007

Molecular Cancer Therapeutics

116

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We investigated whether Rad51 overexpression plays a role in soft tissue sarcoma (STS) chemoresistance as well as the regulatory mechanisms underlying its expression. The studies reported here show that Rad51 protein is overexpressed in a large panel of human STS specimens. Human STS cell lines showed increased Rad51 protein expression, as was also observed in nude rat STS xenografts. STS cells treated with doxorubicin exhibited up-regulation of Rad51 protein while arrested in the S-G 2 phase of the cell cycle. Treatment with anti-Rad51 small interfering RNA decreased Rad51 protein expression and increased chemosensitivity to doxorubicin. Because we previously showed that reintroduction of wild-type p53 (wtp53) into STS cells harboring a p53 mutation led to increased doxorubicin chemosensitivity, we hypothesized that p53 participates in regulating Rad51 expression in STS. Reintroduction of wtp53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression. Using luciferase reporter assays, we showed that reconstitution of wtp53 function decreased Rad51 promoter activity. Deletion constructs identified a specific Rad51 promoter region containing a p53-responsive element but no p53 consensus binding site. Electrophoretic mobility shift assays verified activator protein 2 (AP2) binding to this region and increased AP2 binding to the promoter in the presence of wtp53. Mutating this AP2 binding site eliminated the wtp53 repressive effect. Furthermore, AP2 knockdown resulted in increased Rad51 expression. In light of the importance of Rad51 in modulating STS chemoresistance, these findings point to a potential novel strategy for molecular-based treatments that may be of relevance to patients burdened by STS. [Mol Cancer Ther 2007;6(5):1650 -60]

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Section: Introductionmentioning

confidence: 99%

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

Hannay

Liu

Zhu

et al. 2007

Molecular Cancer Therapeutics

116

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“…Overexpression of Rad51 protein in tumour cells renders them resistant against cytotoxic drugs like Cisplatin. Importantly, Ohnishi et al (1998) found that treatment of monolayer cultures of tumour cells with Rad51-specific antisense oligonucleotides renders those cells radiosensitive. Rad51 protein is highly expressed in tumour cell nuclei of several solid carcinomas (Maacke et al, 2000a).…”

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confidence: 99%

High-level expression of Rad51 is an independent prognostic marker of survival in non-small-cell lung cancer patients

et al. 2005

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High-level expression of Rad51, a key factor in homologous recombination, has been observed in a variety of human malignancies. This study was aimed to evaluate Rad51 expression to serve as prognostic marker in non-small-cell lung cancer (NSCLC). A total of 383 non-small-cell lung tumours were analysed immunohistochemically on NSCLC tissue microarrays. High-level Rad51 expression was observed in 29.4% (100 out of 340) of cases. Patients whose tumours displayed high-level Rad51 expression showed a significantly shorter median survival time of 19 vs 68 months (Po0.0001, log-rank test). Similarly T status, N status, M status, clinical stage and histological tumour grade were significant prognostic markers in univariate Cox survival analysis. Importantly, Rad51 expression (Po0.0001) together with tumour differentiation (Po0.009), clinical stage (P ¼ 0.004) and N status (P ¼ 0.0001) proved to be independent prognostic parameters in multivariate analysis. Rad51 expression predicted the outcome of squamous cell cancer as well as adenocarcinoma of the lung. Our results suggest that Rad51 expression provides additional prognostic information for surgically treated NSCLC patients. We hypothesise that the decreased survival of NSCLC patients with high-level expression of Rad51 is related to an enhanced propensity of tumour cells for survival, antiapoptosis and chemo-/radioresistance.

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“…A cell-cycle-dependent effect of Rad51 protein accumulation has been shown, with a peak in the S and G2 phases, in which the repair of Dsb primarily takes place via homologous recombination (Flygare et al, 1996). A number of approaches have shown that reduction in Rad51 levels via antisense oligonucleotides (Taki et al, 1996;Ohnishi et al, 1998), ribozymes (Collis et al, 2001) or drugs (Russell et al, 2003) increased the radiation sensitivity of tumour cell lines.…”

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confidence: 99%

Targeting of Rad51-dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines

et al. 2005

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The aim of the present work was to study the role of Rad51-dependent homologous recombination in the radiation response of non-small-cell lung cancer (NSCLC) cell lines. A dose-and time-dependent increase in the formation of Rad51 and g-H2AX foci with a maximum at about 4 and 1 h after irradiation, followed by a decrease, has been found. The relative fraction of cells with persisting Rad51 foci was 20 -30% in radioresistant and 60 -80% in radiosensitive cell lines. In comparison, a higher fraction of residual Dsb was evident in cell lines with nonfunctional p53. Transfection with As-Rad51 significantly downregulates radiation-induced formation of Rad51 foci and increases apoptosis, but did not influence the rejoining of DNA double-strand breaks. Interestingly, wortmannin, a well-known inhibitor of nonhomologous end-joining, also inhibits Rad51 foci formation. In general, there was no correlation between the clonogenic survival at 2 Gy and the percentage of initial Rad51 or g-H2AX foci after ionising radiation (IR). The most reliable predictive factor for radiosensitivity of NSCLC cell lines was the relative fraction of Rad51 foci remaining at 24 h after IR. Although most of the Rad51 foci are co-localised with g-H2AX foci, no correlation of the relative fraction of persisting g-H2AX foci and SF2 is evident.

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In Vitroandin VivoPotentiation of Radiosensitivity of Malignant Gliomas by Antisense Inhibition of the RAD51 Gene

Cited by 104 publications

References 20 publications

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

High-level expression of Rad51 is an independent prognostic marker of survival in non-small-cell lung cancer patients

Targeting of Rad51-dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines

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