Abstract
Ovarian cancer (OC) is the most lethal of the gynecologic cancers, and platinum-based treatment is a part of the standard first-line chemotherapy regimen. However, rapid development of acquired cisplatin resistance remains the main cause of treatment failure, and the underlying mechanism of resistance in OC treatment remains poorly understood. Faced with this problem, our aim in this study was to generate cisplatin-resistant (CisR) OC cell models in vitro and investigate the role of epithelial–mesenchymal transition (EMT) transcription factor Twist on acquired cisplatin resistance in OC cell models. To achieve this aim, OC cell lines OV-90 and SKOV-3 were exposed to cisplatin using pulse dosing and stepwise dose escalation methods for a duration of eight months, and a total of four CisR sublines were generated, two for each cell line. The acquired cisplatin resistance was confirmed by determination of 50% inhibitory concentration (IC50) and clonogenic survival assay. Furthermore, the CisR cells were studied to assess their respective characteristics of metastasis, EMT phenotype, DNA repair and endoplasmic reticulum stress-mediated cell death. We found the IC50 of CisR cells to cisplatin was 3–5 times higher than parental cells. The expression of Twist and metastatic ability of CisR cells were significantly greater than those of sensitive cells. The CisR cells displayed an EMT phenotype with decreased epithelial cell marker E-cadherin and increased mesenchymal proteins N-cadherin and vimentin. We observed that CisR cells showed significantly higher expression of DNA repair proteins, X-ray repair cross-complementing protein 1 (XRCC1) and poly (ADP-ribose) polymerases 1 (PARP1), with significantly reduced endoplasmic reticulum (ER) stress-mediated cell death. Moreover, Twist knockdown reduced metastatic ability of CisR cells by suppressing EMT, DNA repair and inducing ER stress-induced cell death. In conclusion, we highlighted the utilization of an acquired cisplatin resistance model to identify the potential role of Twist as a therapeutic target to reverse acquired cisplatin resistance in OC.
Highlights
The most lethal gynecological malignancy, ovarian cancer (OC) is the third most prevalent after cervical and uterine cancers and is the fifth leading cause of cancer-associated death in women worldwide [1,2]
It has been demonstrated that acquired cisplatin resistance is associated with overexpression of ATP-binding cassette (ABC) transporters, reduced drug accumulation, insufficient DNA binding, increased DNA repair, and altered expression and activation of genes involved in cell death pathways [9,13,14,15,16,17,18]
Our results demonstrated that the extracellular matrix (ECM)-like fibronectin was associated with a decreased sensitivity to cisplatin-based drug treatment, as CisR cells displayed higher cell-ECM adhesion compared to the parental OC cells (Figure S5)
Summary
The most lethal gynecological malignancy, ovarian cancer (OC) is the third most prevalent after cervical and uterine cancers and is the fifth leading cause of cancer-associated death in women worldwide [1,2]. Significant treatment improvements have been achieved through platinum-based chemotherapy, for which the initial response rate is more than 80%, the 5-year survival rate for more than 75% of patients with advanced OC is only 15–25% [3,7]. The process of acquiring cisplatin resistance is not fully understood, but it is believed that tumors resistances to cisplatin are resistance to the other platinum drugs [11,12]. It has been demonstrated that acquired cisplatin resistance is associated with overexpression of ATP-binding cassette (ABC) transporters, reduced drug accumulation, insufficient DNA binding, increased DNA repair, and altered expression and activation of genes involved in cell death pathways [9,13,14,15,16,17,18]. It has been reported that cisplatin-resistant oral squamous cell carcinoma cells upregulate the activity of multidrug resistance protein 1 (MDR1) or breast cancer resistance protein (BCRP) associated with EMT [21]
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