Inhibition of homologous recombination repair by Mirin in ovarian cancer ameliorates carboplatin therapy response in vitro
Language English Country England, Great Britain Media print
Document type Journal Article
Grant support
19-10543S
Czech Science Foundation
PubMed
38099488
DOI
10.1093/mutage/gead036
PII: 7473603
Knihovny.cz E-resources
- Keywords
- DNA repair, MRE11, cancer therapy, chemoresistance, ovarian cancer,
- MeSH
- Drug Resistance, Neoplasm * genetics drug effects MeSH
- MRE11 Homologue Protein * genetics metabolism antagonists & inhibitors MeSH
- Carboplatin * pharmacology therapeutic use MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Ovarian Neoplasms * drug therapy genetics pathology MeSH
- Antineoplastic Agents * pharmacology MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Recombinational DNA Repair * drug effects MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- MRE11 Homologue Protein * MeSH
- Carboplatin * MeSH
- MRE11 protein, human MeSH Browser
- Antineoplastic Agents * MeSH
Chemoresistance poses one of the most significant challenges of cancer therapy. Carboplatin (CbPt) is one of the most used chemotherapeutics in ovarian cancer (OVC) treatment. MRE11 constitutes a part of homologous recombination (HR), which is responsible for the repair of CbPt-induced DNA damage, particularly DNA crosslinks. The study's main aim was to address the role of HR in CbPt chemoresistance in OVC and to evaluate the possibility of overcoming CbPt chemoresistance by Mirin-mediated MRE11 inhibition in an OVC cell line. Lower expression of MRE11 was associated with better overall survival in a cohort of OVC patients treated with platinum drugs (TCGA dataset, P < 0.05). Using in vitro analyses, we showed that the high expression of HR genes drives the CbPt chemoresistance in our CbPt-resistant cell line model. Moreover, the HR inhibition by Mirin not only increased sensitivity to carboplatin (P < 0.05) but also rescued the sensitivity in the CbPt-resistant model (P < 0.05). Our results suggest that MRE11 inhibition with Mirin may represent a promising way to overcome OVC resistance. More therapy options will ultimately lead to better personalized cancer therapy and improvement of patients' survival.
1st Faculty of Medicine Charles University 121 08 Prague Czech Republic
3rd Faculty of Medicine Charles University 100 00 Prague Czech Republic
Biomedical Center Faculty of Medicine in Pilsen Charles University 323 00 Pilsen Czech Republic
Faculty of Science Charles University 128 00 Prague Czech Republic
Toxicogenomics Unit National Institute of Public Health 100 00 Prague Czech Republic
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