Drug resistance‐related gene targets and molecular mechanisms in the A2780/Taxol‐resistant epithelial ovarian cancer cell line
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ABSTRACT:
SUBMITTER: Yang R
PROVIDER: S-EPMC10996034 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Project description:To investigate the gene targets associated with paclitaxel resistance in EOC, we cultured A2780 and paclitaxel resistant A2780 (A2780-Taxol) cell lines.
2023-06-01 | GSE230667 | GEO
Project description:Drug Resistance-Related Gene Targets and Molecular Mechanisms in the A2780 Paclitaxel-Resistant Cell Line of Epithelial Ovarian Cancer
| PRJNA962095 | ENA
Project description:BackgroundOvarian cancer is one of the most lethal gynecological malignancies, in which platinum resistance is a common cause of its relapse and death. Glycosylation has been reported to be involved in drug resistance, and glycomic analyses of ovarian cancer may improve our understanding of the mechanisms underlying cancer cell drug resistance and provide potential biomarkers and therapeutic targets.MethodsThe serous ovarian cancer cell line A2780 and its platinum-resistant counterpart A2780-cp were used in this study. We performed a lectin array analysis to compare the glycosylation patterns of the two cell lines, a gene expression array was employed to probe the differences in glycogenes. Furthermore, the results were verified by lectin blots.ResultsA2780-cp cell exhibited stronger intensities of Lens culinaris (LCA) Canavalia ensiformis (ConA), and Lycopersicon esculentum (LEL) and weaker intensities of Sambucus nigra (SNA) lectins. The gene expression array analysis revealed increased expression of Fut8, B3gnt4, B3gnt5, B4galt2 and decreased expression of Fut1 and ST6GalNAc 6 expression were evident in the A2780-cp cells. The lectin blot confirmed the differences in LCA, ConA, SNA and LEL between the A2780 and A2780-cp cells.ConclusionsThe combination of the lectin and gene expression analyses showed that the levels of core fucosylation and poly-LacNAc were increased in the A2780-cp cells and the levels of Fuc α1-2(gal β1-4) GlcNAc and α2-6-linked sialic structures were decreased in the A2780-cp cells. These glycans represent potential biomarkers and might be involved in the mechanism of drug resistance in ovarian cancer.
| S-EPMC5442857 | biostudies-literature
Project description:BackgroundOvarian cancer is a significant cancer-related cause of death in women worldwide. The most used chemotherapeutic regimen is based on carboplatin (CBDCA). However, CBDCA resistance is the main obstacle to a better prognosis. An in vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize cellular and molecular changes of induced CBDCA-resistant ovarian cancer cell line A2780.MethodsThe cell selection strategy used in this study was a dose-per-pulse method using a concentration of 100 μM for 2 h. Once 20 cycles of exposure to the drug were completed, the cell cultures showed a resistant phenotype. Then, the ovarian cancer cell line A2780 was grown with 100 μM of CBDCA (CBDCA-resistant cells) or without CBDCA (parental cells). After, a drug sensitivity assay, morphological analyses, cell death assays and a RNA-seq analysis were performed in CBDCA-resistant A2780 cells.ResultsMicroscopy on both parental and CBDCA-resistant A2780 cells showed similar characteristics in morphology and F-actin distribution within cells. In cell-death assays, parental A2780 cells showed a significant increase in phosphatidylserine translocation and caspase-3/7 cleavage compared to CBDCA-resistant A2780 cells (P < 0.05 and P < 0.005, respectively). Cell viability in parental A2780 cells was significantly decreased compared to CBDCA-resistant A2780 cells (P < 0.0005). The RNA-seq analysis showed 156 differentially expressed genes (DEGs) associated mainly to molecular functions.ConclusionCBDCA-resistant A2780 ovarian cancer cells is a reliable model of CBDCA resistance that shows several DEGs involved in molecular functions such as transmembrane activity, protein binding to cell surface receptor and catalytic activity. Also, we found that the Wnt/β-catenin and integrin signaling pathway are the main metabolic pathway dysregulated in CBDCA-resistant A2780 cells.
| S-EPMC6427839 | biostudies-literature
Project description:Purpose. Several studies have shown that natural compounds like resveratrol or ellagic acid have anticancer and antioxidant properties and can stimulate apoptosis in many cancer cell lines. The aim of this study was to elucidate if resveratrol or ellagic acid, respectively, could improve the efficacy of cisplatin in ovarian cancer. Methods. As a cellular resistance model, the epithelial ovarian cancer cell line A2780 and its cisplatin-resistant subclone A2780CisR were used. A2780CisR was obtained by intermittent treatment of A2780 with cisplatin for 26 weekly cycles and showed a 4-6-fold increased resistance towards cisplatin compared to A2780. Results. Pretreatment with resveratrol or ellagic acid 48 h prior to treatment with cisplatin showed a moderate enhancement of cisplatin cytotoxicity in A2780CisR cells (shift factors were 1.6 for ellagic acid and 2.5 for resveratrol). However, intermittent treatment of A2780 with cisplatin for 26 weekly cycles in permanent presence of resveratrol or ellagic acid, respectively, completely prevented the development of cisplatin resistance. The generated cell lines named A2780Resv and A2780Ellag displayed functional characteristics (migration, proliferation, apoptosis, activation of ErbB3, ROS generation) similar to the parental cell line A2780. Conclusion. In conclusion, weekly intermittent treatment cycles of cisplatin-sensitive ovarian cancer cells with cisplatin retain cisplatin chemosensitivity in permanent presence of ellagic acid or resveratrol, respectively, whereas clinically relevant cisplatin chemoresistance develops in the absence of ellagic acid or resveratrol. Use of natural phenolic compounds may thus be a promising approach to prevent cisplatin resistance in ovarian cancer.
| S-EPMC4749356 | biostudies-literature
Project description:In the United States, over 100,000 women are diagnosed with a gynecologic malignancy every year, with ovarian cancer being the most lethal. One of the hallmark characteristics of ovarian cancer is the development of resistance to chemotherapeutics. While the exact mechanisms of chemoresistance are poorly understood, it is known that changes at the cellular and molecular level make chemoresistance challenging to treat. Improved therapeutic options are needed to target these changes at the molecular level. Using a precision medicine approach, such as gene therapy, genes can be specifically exploited to resensitize tumors to therapeutics. This review highlights traditional and novel gene targets that can be used to develop new and improved targeted therapies, from drug efflux proteins to ovarian cancer stem cells. The review also addresses the clinical relevance and landscape of the discussed gene targets.
| S-EPMC9777152 | biostudies-literature
Project description:ObjectiveMultidrug resistance is the major cause of failure of many chemotherapeutic agents. While resistance can arise from several factors, it is often dominated by drug efflux mediated by P-glycoprotein (P-gp), a membrane-bound polysubstrate export pump expressed at high levels in resistant cells. While co-administration of pump inhibitors and a drug could suppress efflux, this two-drug strategy has not yet advanced to therapy. We recently demonstrated that the reversible attachment of a guanidinium-rich molecular transporter, polyarginine, to a drug provides a conjugate that overcomes efflux-based resistance in cells and animals. This study is to determine whether this strategy for overcoming resistance is effective against human disease.MethodsTumor samples from ovarian cancer patients, both malignant ascites cells and dissociated solid tumor cells, were exposed to Taxol-oligoarginine conjugates designed to release free drug only after cell entry. Cell viability was determined via propidium-iodide uptake by flow cytometry. To analyze bystander effect, toxicity of the drug conjugates was also tested on peripheral blood leucocytes.ResultsHuman ovarian carcinoma specimens resistant to Taxol in vitro demonstrated increased sensitivity to killing by all Taxol-transporter conjugates tested. These studies also show that the drug conjugates were not significantly more toxic to normal human peripheral blood leukocytes than Taxol.ConclusionsThese studies with human tumor indicate that oligoarginine conjugates of known drugs can be used to overcome the efflux-based resistance to the drug, providing a strategy that could improve the treatment outcomes of patients with efflux-based drug-resistance.
| S-EPMC3883629 | biostudies-literature
Project description:Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.
| S-EPMC4059749 | biostudies-literature
Project description:Ovarian cancer therapy remains a challenge for human health, partly due to chemotherapy resistance. Understanding the molecular mechanisms underlying this resistance is crucial. Therefore, to identify genes involved in cisplatin resistance in ovarian cancer, RNA-seq analysis of A2780cp (cisplatin-resistant) and A2780 (cisplatin-sensitive) cell lines was performed, revealing 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) as a differentially expressed candidate gene. First, MTT analysis confirmed the drug resistance of A2780cp and the sensitivity of A2780 cell lines. Subsequent reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses revealed elevated AGPAT3 and mTOR expression in A2780cp cells compared with A2780 cells. Additionally, western blotting showed increased p-mTOR (phospho-mTOR)/mTOR and p-S6K (phospho-S6K)/S6K ratios in A2780cp cells. The overexpression of AGPAT3 in A2780 cells led to increased p-mTOR/mTOR and p-S6K/S6K ratios and increased IC50 values, as shown by RT-qPCR, western blotting, and MTT analysis. Conversely, shRNA-mediated downregulation of AGPAT3 resulted in reduced p-mTOR/mTOR and p-S6K/S6K ratios. At the cellular level, AGPAT3 overexpression in A2780 cells increased survival rates, decreased apoptosis, and caused G2/M cell cycle arrest under cisplatin treatment, as detected by apoptosis assay, and cell cycle flow cytometry analysis. Overall, we conclude that AGPAT3 is involved in cisplatin resistance in A2780cp cells and propose that targeting this gene or its enzymatic product could help overcome drug resistance.
| S-EPMC11892817 | biostudies-literature
Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy owing to relapse caused by resistance to chemotherapy. We previously reported that cluster of differentiation 109 (CD109) expression is positively correlated with poor prognosis and chemoresistance in patients with EOC. To further explore the role of CD109 in EOC, we explored the signaling mechanism of CD109-induced drug resistance. We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. In EOC cells (A2780 and A2780-R), the expression level of CD109 was positively correlated with the expression level of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, and paclitaxel (PTX) resistance. Using a xenograft mouse model, it was confirmed that PTX administration in xenografts of CD109-silenced A2780-R cells significantly attenuated in vivo tumor growth. The treatment of CD109-overexpressed A2780 cells with cryptotanshinone (CPT), a signal transducer and activator of transcription 3 (STAT3) inhibitor, inhibited the CD109 overexpression-induced activation of STAT3 and neurogenic locus notch homolog protein 1 (NOTCH1), suggesting a STAT3-NOTCH1 signaling axis. The combined treatment of CD109-overexpressed A2780 cells with CPT and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a NOTCH inhibitor, markedly abrogated PTX resistance. These results suggest that CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.
| S-EPMC10299649 | biostudies-literature