scholarly journals MTA1 promotes cell proliferation via DNA damage repair in epithelial ovarian cancer

2014 ◽  
Vol 13 (4) ◽  
pp. 10269-10278 ◽  
Author(s):  
Q.Y. Yang ◽  
J.H. Li ◽  
Q.Y. Wang ◽  
Y. Wu ◽  
J.L. Qin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals PARP Inhibitors for Ovarian Cancer: Current Indications, Future Combinations, and Novel Assets in Development to Target DNA Damage Repair

2020 ◽  
pp. e116-e131
Author(s):  
Panagiotis A. Konstantinopoulos ◽  
Stephanie Lheureux ◽  
Kathleen N. Moore
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Repair ◽  
Parp Inhibitors ◽  
Ongoing Research ◽  
Epithelial Cancers ◽  
Combination Strategies ◽  
Damage Repair ◽  
Target Dna

PARP inhibitors (PARPIs) have revolutionized the treatment of epithelial ovarian cancer, first for BRCA-associated cancer, and, recently, for all epithelial cancers of serous or high-grade endometrioid subtypes in the front line. Although there is hope that PARPIs will help prevent recurrences when used following frontline maintenance, cancer will still recur in most women, and the need for active combination strategies as well as continued development of novel assets, either as monotherapy or in combination, will be urgently needed. This review article discusses the current indications for PARPIs in both frontline and recurrent settings, current research in combination approaches, and finally, ongoing research on novel methods to target DNA damage response in an effort to exploit the common susceptibility to DNA damage repair in epithelial ovarian cancer and improve outcomes for patients.

scholarly journals MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway

2019 ◽  
Vol 316 (3) ◽  
pp. C299-C311 ◽  
Author(s):  
Jing Luo ◽  
Zhong-Zhou Si ◽  
Ting Li ◽  
Jie-Qun Li ◽  
Zhong-Qiang Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Replication Protein ◽  
Repair Pathway ◽  
Related Factors ◽  
Damage Repair ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

scholarly journals NUSAP1 Enhances Drug Resistance By Binding to RAD51 through DNA Damage Repair Pathway in Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Yang Han ◽  
Ya Zhang ◽  
Xinting Hu ◽  
Xiang Sun ◽  
Xin Wang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Drug Resistance ◽  
Dna Damage Repair ◽  
Repair Process ◽  
Lymphocytic Leukemia ◽  
Repair Pathway ◽  
Damage Repair

Introduction: Enhanced DNA damage repair effect is an important mechanism for drug-resistance in chronic lymphocytic leukemia (CLL). Moreover, the ability of cancer cells to repair under radiation or chemotherapy drug induced DNA damage also serves as one of the mechanisms for therapy resistance. It is reported that nucleolar and spindle associated protein 1 (NUSAP1), a microtubule binding protein, has been involved in DNA damage repair process and plays important roles in the development, progression, and metastasis in several types of cancer. However, its role and mechanism in the development of CLL are still unclear. Methods: Expression levels of NUSAP1 mRNA and protein in CLL cell lines and patient specimens were detected by qRT-PCR and Western blot, and Kaplan-Meier survival curve and overall survival were analyzed by log-rank test. Peripheral blood samples from de novo CLL patients and healthy volunteers were collected with informed consents at the Department of Hematology in Shandong Provincial Hospital Affiliated to Shandong University (SPHASU). Microarray datasets GSE22762 were obtained from Gene Expression Omnibus. With altering NUSAP1 expression by lentivirus-transfected cells in vitro, the effects of NUSAP1 on cell proliferation, apoptosis and cycle were detected by CCK8, Annexin V-PE /7AAD staining and PI/RNase staining respectively. Bioinformatics analysis, luciferase reporter analysis, immunoprecipitation and were applied to discern and examine the relationship between NUSAP1 and its potential targets. Results: According to clinical specimens and bioinformatics analysis, the expression level of NUSAP1 gene in samples of CLL patients was significantly increased than that of healthy donors (P<0.05) (Figure A). Besides, the results indicated that the OS of patients with highly expressed NUSAP1 was significantly worse than in patients with low expression with the statistical analysis database GSE22762. mRNA and protein expression levels of NUSAP1 were significantly higher in CLL cell lines than in PBMCs from healthy donors (Figure C). Our findings indicated that NUSAP1 knockdown notably inhibited cell proliferation when compared with the Scramble group (Figure D). Moreover, the amounts of DNA fragmentation of the apoptotic cells were remarkably increased by NUSAP1 shRNA in MEC-1 and EHEB cells when compared with the Scramble group (Figure E). In addition, after knocking down NUSAP1, MEC-1 and EHEB cells were blocked in G0/G1 phase (Figure F). Moreover, addition to fludarabine or ibrutinib with shNUSAP1 group showed enhanced cytotoxicity in CLL cells (Figure G). The differential genes were analyzed via RNA-seq between Scramble and ShNUSAP1 group. Intriguingly, annotations of gene ontology (GO) analysis indicated that NUSAP1 was closely related to biological processes including cell cycle and response to drug. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that NUSAP1 were enriched in pathways in cancer, DNA replication and cell cycle. Gene set enrichment analysis (GSEA) implicated that NUSAP1 was functionally enriched in DNA replication, cell cycle and proteasome (Figure H). Immunofluorescence showed that NUSAP1 was mainly distributed in the cell nucleus, and the expression level of RAD51 was positively correlated with the change of NUSAP1 expression (Figure I). Surppression of NUSAP1 inhibited the action of proteins in DNA damage repair pathway (Figure J). Through COIP, NUSAP1 was identified to bind with RAD51 and play an important role in DNA damage repair pathway (Figure K). Hence, NUSAP1 participates in the DNA damage repair process and enhances the drug resistance in CLL. Conclusions: This study first demonstrated that the high expression of NUSAP1 in CLL patients is associated with poor prognosis through database analysis and experiments in vitro. Interference of NUSAP1 expression led to a slower CLL cell proliferation and a higher apoptosis rate, meanwhile induced the G1 phase arrest. Collectively, our findings demonstrated that NUSAP1 contributes to DNA damage repairing by binding to RAD51 and enhances drug resistance in CLL. Therefore, NUSAP1 is expected to be a potential target for the treatment of CLL with drug-resistance. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Bruceine D and Afatinib Combination Inhibits Ovarian Cancer Cells Proliferation and Migration Through DNA Damage Repair and EGFR Pathway

2021 ◽  
Author(s):  
Feng Lin ◽  
Ju-fan Zhu ◽  
Luo Wang ◽  
Yuan-jun Yang ◽  
Ru-ru Zheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Dna Damage Repair ◽  
Egfr Signaling ◽  
Damage Repair ◽  
And Migration ◽  
Proliferation And Migration

Abstract Owing to the high rates of relapse and migration, ovarian cancer has been recognized as the most lethal gynecological malignancy worldwide. The activity of the EGFR signaling pathway is frequently associated with ovarian cancer cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in ovarian cancer patients failed to achieve satisfactory therapeutic effects. In this study, we identified that Bruceine D and EGFR inhibitor, afatinib, combination resulted in synergistic anti- ovarian cancer effects. The results indicated that compared with one of both drugs alone, the combination of Bruceine D and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of Bruceine D and afatinib possessed a stronger ability to inhibit the ovarian cancer cell adhesion and migration than treatment with Bruceine D or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against ovarian cancer treatment. The results support the potential of Bruceine D and afatinib combination as a therapeutic strategy for ovarian cancer patients.

scholarly journals Inhibition of ATR-Chk1 signaling blocks DNA double-strand-break repair and induces cytoplasmic vacuolization in metastatic osteosarcoma

2020 ◽  
Vol 12 ◽  
pp. 175883592095690 ◽  
Author(s):  
Xiaoyang Li ◽  
Dylan C. Dean ◽  
Gregory M. Cote ◽  
Lee Zou ◽  
Francis J. Hornicek ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Therapeutic Target ◽  
Ex Vivo ◽  
Dna Damage Repair ◽  
Parp Cleavage ◽  
Dependent Manner ◽  
Cytoplasmic Vacuolization ◽  
Damage Repair ◽  
Metastatic Osteosarcoma

Background: Ataxia-telangiectasia and Rad3 related protein kinase (ATR) is an essential regulator of the DNA damage response in various cancers; however, its expression and roles in osteosarcoma are unclear. We therefore chose to evaluate the significance and mechanism of ATR in metastatic osteosarcoma, as well as its potential to be a therapeutic target. Methods: The osteosarcoma tissue microarrays constructed from 70 patient specimens underwent immunohistochemistry to quantify ATR and activated phospho-ATR (pATR) expression and their correlation with clinical outcomes. ATR sublocalization within the metastatic osteosarcoma cells was confirmed by immunofluorescence assay. Cell proliferation, apoptosis, and migration were evaluated following treatment with ATR siRNA or the selective inhibitor Berzosertib. Antitumor effects were determined with ex vivo three-dimensional (3D) culture models, and the impacts on the DNA damage repair pathways were measured with Western blotting. Results: Elevated ATR and activated pATR expression correlated with shorter patient survival and less necrosis following neoadjuvant chemotherapy. Intranuclear sublocalization of ATR and pATR suggested a mechanism related to DNA replication. ATR knockdown with siRNA or inhibition with Berzosertib suppressed cell proliferation in a time- and dose-dependent manner and induced apoptosis. In addition, ATR inhibition decreased Chk1 phosphorylation while increasing γH2AX expression and PARP cleavage, consistent with the interference of DNA damage repair. The ATR inhibitor Berzosertib also produced the characteristic cytoplasmic vacuolization preceding cell death, and suppressed ex vivo 3D spheroid formation and cell motility. Conclusion: The faithful dependence of cells on ATR signaling for survival and progression makes it an emerging therapeutic target in metastatic osteosarcoma.

Association of high tumor mutation (TMB) with DNA damage repair (DDR) alterations and better prognosis in ovarian cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 5512-5512 ◽  
Author(s):  
Wenjuan Tian ◽  
Boer Shan ◽  
Yuzi Zhang ◽  
Yulan Ren ◽  
Shanhui Liang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair
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