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

Sak, Ali; Stueben, G; Groneberg, Michael; Böcker, Wilfried; Stuschke, Martin

doi:10.1038/sj.bjc.6602457

Cited by 56 publications

(55 citation statements)

References 40 publications

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“…Ku70, Ku86, and DNA-dependent protein kinase catalytic subunit are key proteins that participate in nonhomologus end joining pathway, which is especially important for repairing the radiation-induced double-strand breaks that are responsible for loss of clonogenic cell survival (20 -22). Down-regulation of these key DNA repair proteins has been linked with an enhanced radioresponse (29,30). In our study, levels of Ku70 and Ku86 proteins were suppressed in A375 cells treated with Vorinostat in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 51%

Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci

Munshi¹,

Tanaka²,

Hobbs³

et al. 2006

Molecular Cancer Therapeutics

216

174

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Vorinostat (suberoylanilide hydroxamic acid) is the prototype of a family of hybrid polar compounds that can induce growth arrest in transformed cells and shows promise for the treatment of cancer. Vorinostat specifically binds to and inhibits the activity of histone deacetylases resulting in acetylation of nucleosomal histones and an activation of gene transcription. Because histone deacetylases modulate chromatin structure and gene expression, both of which can influence radioresponse, this study was designed to examine the capacity of Vorinostat to influence radiation response in human tumor cells and investigate the mechanism underlying these interactions. Vorinostat induced hyperacetylation of histone H4 in a dose-dependent manner. We tested its ability to radiosensitize three human tumor cell lines (A375, MeWo, and A549) using clonogenic cell survival assays. Clonogenic cell survival assay showed that Vorinostat significantly radiosensitized all three tumor cell lines, substantially reducing the surviving fraction at 2 Gy. We examined potential mechanisms that may contribute to the enhanced radiation response induced by Vorinostat. Vorinostat and radiation alone did not induce apoptosis in the melanoma cell line. However, enhanced apoptosis was observed when cells were exposed to both Vorinostat and radiation, suggesting that Vorinostat renders tumor cells more susceptible to radiation-induced apoptosis. Results from DNA damage repair analysis in cultured A375 cells showed that Vorinostat had a strong inhibitory effect on the nonhomologous end joining pathway after radiation. A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis. We also examined ;-H2AX phosphorylation as a predictive marker of radiotherapy response to Vorinostat and observed that the combination of Vorinostat and radiation caused a prolongation of expression of DNA repair proteins such as ;-H2AX. Overall, we conclude that Vorinostat enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation.

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Section: Discussionmentioning

confidence: 51%

Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci

Munshi¹,

Tanaka²,

Hobbs³

et al. 2006

Molecular Cancer Therapeutics

216

174

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show abstract

“…(55). Targeting a number of DNA repair proteins such as RAD51, XRCC4 and ATM has also been shown to increase radiation sensitivity in tumour cell lines (56)(57)(58). In our study, tumours could be sub-classified on the basis of expression of genes with roles in DNA repair and there was a numeric better therapeutic response to irradiation in patients with lowest expression of DNA repair genes (Group 1B), and poorer response in patients with highest expression (Group 1A).…”

Section: 5 -------------------------------------------------C -----mentioning

confidence: 73%

Gene expression profiling of archival tongue squamous cell carcinomas provides sub-classification based on DNA repair genes

Rentoft

Laurell²,

Coates³

et al. 2009

Int J Oncol

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Abstract.A subgroup of patients with squamous cell carcinoma of the head and neck (SCCHN) comprise young persons under the age of 40, who have not been heavily exposed to the classical risk factors, smoking and alcohol. The number of SCCHN in young adults, particularly tongue tumours, is increasing in several parts of the world. Here we employed a novel gene expression array methodology specifically developed for analysis of degraded RNA and investigated the expression of 502 cancer-related genes in archival paraffin-embedded SCCHN of the tongue from young (≤40) and elderly patients (≥50). Genes detected as de-regulated in tumours compared to non-malignant controls were in concordance with results from earlier studies of fresh frozen material. No genes were detected as significantly differentially expressed between young and old patients suggesting that the overall pathobiology of SCCHN is similar in young and old. Unsupervised clustering divided tumours into three groups, irrespective of age, where several differentially expressed DNA repair genes were a prominent separation factor. High levels of DNA repair genes associated with impaired therapeutic response to radiation, suggesting that DNA repair genes play a role in clinical outcome after radiotherapy.

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“…Previous studies have also shown that the PI3K inhibitor wortmannin can prevent radiation-induced apoptosis and the formation of Rad51 foci in NSCLC (Sak et al, 2005). In addition, there is evidence indicating that c-Abl is involved in increasing Rad51 transcription.…”

Section: Downloaded Frommentioning

confidence: 90%

Down-Regulation of Rad51 Expression Overcomes Drug Resistance to Gemcitabine in Human Non–Small-Cell Lung Cancer Cells

Tsai

Kuo²,

Chiu³

et al. 2010

J Pharmacol Exp Ther

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Gemcitabine (2Ј,2Ј-difluorodeoxycytidine), a deoxycytidine analog, and erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, are used clinically to treat patients with nonsmall-cell lung cancer (NSCLC). However, the molecular mechanisms for the drug resistance of gemcitabine in NSCLC cells are poorly understood. In this study, we used constructs containing human Rad51 cDNA or specific Rad51 small interfering RNA (siRNA) to examine the role of Rad51 in chemoresistance of gemcitabine in three different human NSCLC cell lines. Exposure of human NSCLC cell lines to gemcitabine increased the phosphorylation levels of mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 and AKT in a time-and dose-dependent manner, which was accompanied by an induction of Rad51 mRNA and protein expression. Gemcitabine increased the expression of Rad51 by increasing its mRNA and protein stability. Blockage of ERK1/2 or AKT activation by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126; MKK1/2 inhibitor) or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002; phosphatidyl inositol 3-kinase inhibitor), respectively, decreased the gemcitabine-induced Rad51 expression. Gemcitabine-induced cytotoxicity was significantly increased using siRNA depletion of Rad51 or blockage of ERK1/2 and AKT activation. Erlotinib enhanced the gemcitabine-induced cytotoxicity via the inactivation of ERK1/2 and AKT and the down-regulation of Rad51. Enforced expression of constitutively active MKK1/2 or AKT recovered cell viability and Rad51 protein levels that were decreased by the combination of erlotinib and gemcitabine. Suppression of Rad51 expression or the inactivation of ERK1/2 or AKT signaling may be considered potential therapeutic modalities for gemcitabine-resistant lung cancer.

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

Cited by 56 publications

References 40 publications

Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci

Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci

Gene expression profiling of archival tongue squamous cell carcinomas provides sub-classification based on DNA repair genes

Down-Regulation of Rad51 Expression Overcomes Drug Resistance to Gemcitabine in Human Non–Small-Cell Lung Cancer Cells

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