Abstract
BackgroundAmong gynecological cancers, ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer. Therefore, novel strategies are required to improve its poor prognosis. Formation and disassembly of focal adhesions are regulated dynamically during cell migration, which plays an essential role in cancer metastasis. Metastasis is intricately linked with resistance to chemotherapy, but the molecular basis for this link is unknown.MethodsTranswell migration and wound healing migration assays were used to analyze the migration ability of ovarian cancer cells. Real-time recordings by total internal reflection fluorescence microscope (TIRFM) were performed to assess the turnover of focal adhesions with fluorescence protein-tagged focal adhesion molecules. SOCE inhibitors were used to verify the effects of SOCE on focal adhesion dynamics, cell migration, and chemoresistance in chemoresistant cells.ResultsWe found that mesenchymal-like chemoresistant IGROV1 ovarian cancer cells have higher migration properties because of their rapid regulation of focal adhesion dynamics through FAK, paxillin, vinculin, and talin. Focal adhesions in chemoresistant cells, they were smaller and exhibited strong adhesive force, which caused the cells to migrate rapidly. Store-operated Ca2+ entry (SOCE) regulates focal adhesion turnover, and cell polarization and migration. Herein, we compared SOCE upregulation in chemoresistant ovarian cancer cells to its parental cells. SOCE inhibitors attenuated the assembly and disassembly of focal adhesions significantly. Results of wound healing and transwell assays revealed that SOCE inhibitors decreased chemoresistant cell migration. Additionally, SOCE inhibitors combined with chemotherapeutic drugs could reverse ovarian cancer drug resistance.ConclusionOur findings describe the role of SOCE in chemoresistance-mediated focal adhesion turnover, cell migration, and viability. Consequently, SOCE might be a promising therapeutic target in epithelial ovarian cancer.Graphical abstract
Highlights
IntroductionOvarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer
Among gynecological cancers, ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer
We found that focal adhesion assembly and disassembly rates, cell adhesion, and cell migration are higher in Store-operated Ca2+ entry (SOCE)-upregulated chemoresistant ovarian cancer cells
Summary
Ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer. Over 50% of patients diagnosed with ovarian cancer eventually die, making it the leading cause of death among all gynecological cancers [3]. Ovarian cancer is typically not diagnosed until the late-stages (stages III and IV), and this makes its five-year relative survival rate extremely low (approximately 35 and 15% for stages III and IV, respectively). In addition to the difficulty associated with its early detection, ovarian cancer develops drug resistance especially to platinum- and taxane-based drugs [4], and this disease may relapse 2–10 years after treatment. Despite the advances in multidisciplinary treatment, a significant number of patients eventually develop metastatic or recurrent diseases and the overall mortality of ovarian cancer has remained steady over the last 30 years [5]. Chemoresistance is a major obstacle in ovarian cancer therapy, and overcoming chemoresistance is an important goal in ovarian cancer therapy [8]
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