DNA Repair and Cytotoxic Drugs: the Potential Role of RAD51 in Clinical Outcome of Non-Small-Cell Lung Cancer Patients

Nogueira, Augusto; Assis, Joana; Catarino, Raquel; Medeiros, Rui

doi:10.2217/pgs.13.48

Cited by 19 publications

(16 citation statements)

References 104 publications

(84 reference statements)

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“…Rad-51, an important component of DNA homologous recombination system, plays key roles in repairing DNA DSBs which are the predominant lethal lesions induced by irradiation [21]. Survivin, a key regulator of apoptosis pathway, has been reported to be associated with cell survival and maintenance [22].…”

Section: Resultsmentioning

confidence: 99%

Acquisition of radioresistance in docetaxel-resistant human lung adenocarcinoma cells is linked with dysregulation of miR-451/c-Myc-survivin/rad-51 signaling

et al. 2014

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Chemoresistant tumors usually fail to respond to radiotherapy. However, the mechanisms involved in chemo- and radiotherapy cross resistance are not fully understood. Previously, we have identified microRNA (miR)-451 as a tumor suppressor in lung adenocarcinoma (LAD). However, whether miR-451 plays critical roles in chemo- and radiotherapy cross resistance in LAD is unclear. Here, we established two docetaxel-resistant LAD cell models (SPC-A1/DTX and H1299/DTX), and showed that miR-451 was significantly downregulated in docetaxel-resistant LAD cells. Gain - and loss - of - function assays indicated that re-expression of miR-451 could reverse radioresistance of docetaxel-resistant LAD cells both in vitro and in vivo through promoting apoptosis and DNA double-strand breaks (DSBs). The proto-oncogene c-Myc was identified as a direct target of miR-451, and re-expression of miR-451 inhibited survivin and rad-51 expression by reducing the amount of c-Myc protein binding to their promoters. Silencing of c-Myc could phenocopy the effects of miR-451 upregulation, and restoration of c-Myc could partially rescue the effect of miR-451 upregulation on radiosensitivity of docetaxel-resistant LAD cells. Therefore, dysregulation of miR-451/c-Myc-survivin/rad-51 signaling is responsible for radioresistance of docetaxel-resistant LAD cells, and targeting it will be a potential strategy for reversing chemo- and radiotherapy cross resistance of LAD patients.

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Section: Resultsmentioning

confidence: 99%

Acquisition of radioresistance in docetaxel-resistant human lung adenocarcinoma cells is linked with dysregulation of miR-451/c-Myc-survivin/rad-51 signaling

et al. 2014

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“…For this reason, several groups are investigating the use of DNA-repair inhibitors (including ATM inhibitors [ 25 ]) to potentiate the efficacy of IR and genotoxic agents [ 26 – 28 ]. Further, factors involved in the DDR are used as biomarkers to predict responses to chemo- and radiotherapy [ 23 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells

Palmieri

Scarpa

Tessari³

et al. 2016

Oncotarget

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Ran Binding Protein 9 (RanBP9, also known as RanBPM) is an evolutionary conserved scaffold protein present both in the nucleus and the cytoplasm of cells whose biological functions remain elusive.We show that active ATM phosphorylates RanBP9 on at least two different residues (S181 and S603). In response to IR, RanBP9 rapidly accumulates into the nucleus of lung cancer cells, but this nuclear accumulation is prevented by ATM inhibition. RanBP9 stable silencing in three different lung cancer cell lines significantly affects the DNA Damage Response (DDR), resulting in delayed activation of key components of the cellular response to IR such as ATM itself, Chk2, γH2AX, and p53. Accordingly, abrogation of RanBP9 expression reduces homologous recombination-dependent DNA repair efficiency, causing an abnormal activation of IR-induced senescence and apoptosis.In summary, here we report that RanBP9 is a novel mediator of the cellular DDR, whose accumulation into the nucleus upon IR is dependent on ATM kinase activity. RanBP9 absence hampers the molecular mechanisms leading to efficient repair of damaged DNA, resulting in enhanced sensitivity to genotoxic stress. These findings suggest that targeting RanBP9 might enhance lung cancer cell sensitivity to genotoxic anti-neoplastic treatment.

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“…It identifies DNA damage and signals the BRCA1-associated genome surveillance complex (BASC), which loads BRCA2/RAD51 onto double stranded breaks (DBS)[14]. Genomic alterations of BRCA1, BRCA2, and RAD51 are associated with poor prognosis in multiple cancers [15–17]. Conversely, alterations in these genes also correlate with increased response rates (RR) to platinum chemotherapy as they may enhance chemotherapy-induced DNA damage [18–21].…”

Section: Introductionmentioning

confidence: 99%

Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma

Mullane

Werner

Guancial

et al. 2016

Clinical Genitourinary Cancer

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Background Combination platinum chemotherapy is standard first line therapy for metastatic urothelial carcinoma (mUC) patients. Defining platinum response biomarkers for mUC patients, could establish personalize medicine and provide insights into mUC biology. While DNA repair mechanisms are hypothesized to mediate platinum response, we sought to analyze if increased expression of DNA damage genes correlates with a worse overall survival (OS) in mUC patients. Methods We retrospectively identified a clinically annotated cohort of mUC patients, treated with first-line platinum combination chemotherapy. A tissue microarray (TMA) was constructed from formalin fixed paraffin embedded (FFPE) tissue from the pre-treatment primary tumor. Immunohistochemical (IHC) analysis of the following DNA repair proteins; ERCC1, RAD51, BRCA1/2, PAR, and PARP-1, was performed. Nuclear and cytoplasmic expression was analyzed using multispectral image. Nuclear staining was used for the survival analysis. Cox regression evaluated the associations of the percentage of positive nuclear staining and OS in multivariable analysis, controlling for known prognostic variables. Results In a cohort of 104 mUC patients, higher nuclear staining percentage of ERCC1 [HR=2.7 (1.5, 4.9), p=0.0007], RAD51 [HR=5.6 (1.7, 18.3), p=0.005], and PAR [with HR=2.2 (1.1, 4.4) p=0.026] were associated with worse OS. BRCA1, BRCA2, and PARP-1 were not associated with OS (p=0.76, p=0.38, p=0.09). Higher combined ERCC1 and RAD51 nuclear staining were strongly associated with worse OS (p=0.005). Conclusions High nuclear staining percentage of ERCC1, RAD51, and PAR, as assessed by IHC, are correlated with worse OS for mUC patients treated with first line platinum combination chemotherapy, supporting the evidence of DNA repair pathways’ role in the prognosis of mUC. We have also produced new evidence that RAD51 and PAR may play a role in platinum response. Further prospective studies are required to determine the prognostic or predictive nature of these biomarkers in mUC.

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DNA Repair and Cytotoxic Drugs: the Potential Role of RAD51 in Clinical Outcome of Non-Small-Cell Lung Cancer Patients

Cited by 19 publications

References 104 publications

Acquisition of radioresistance in docetaxel-resistant human lung adenocarcinoma cells is linked with dysregulation of miR-451/c-Myc-survivin/rad-51 signaling

Acquisition of radioresistance in docetaxel-resistant human lung adenocarcinoma cells is linked with dysregulation of miR-451/c-Myc-survivin/rad-51 signaling

Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells

Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma

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