Abstract
Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop platinum-resistant disease with poor prognosis. Although reports suggest that integrin-linked kinase (ILK) is a potential target for ovarian cancer treatment, identification of ILK downstream effectors has not been fully explored. The purpose of this study was to investigate the molecular and biological effects of targeting ILK in cisplatin-resistant ovarian cancer. Western blot analysis showed that phosphorylation levels of ILK were higher in cisplatin-resistant compared with cisplatin-sensitive ovarian cancer cells. Further immunohistochemical analysis of ovarian cancer patient samples showed a significant increase in phosphorylated ILK levels in the tumor tissue when compared to normal ovarian epithelium. Targeting ILK by small-interfering RNA (siRNA) treatment reduced cisplatin-resistant cell growth and invasion ability, and increased apoptosis. Differential gene expression analysis by RNA sequencing (RNA-Seq) upon ILK-siRNA transfection followed by Ingenuity Pathway Analysis (IPA) and survival analysis using the Kaplan–Meier plotter database identified multiple target genes involved in cell growth, apoptosis, invasion, and metastasis, including several non-coding RNAs. Taken together, results from this study support ILK as an attractive target for ovarian cancer and provide potential ILK downstream effectors with prognostic and therapeutic value.
Highlights
Ovarian cancer remains a significant cause of female cancer-related deaths, with approximately21,750 new cases and 13,940 deaths for 2020 in the US [1]
Western blot and densitometric analysis of a panel of ovarian cancer cell lines showed that phosphorylation levels of integrin-linked kinase (ILK) (p-ILK; Ser 246) relative to total ILK protein (p-ILK/ILK) were significantly higher in cisplatin-resistant A2780CP20 and OVCAR3CIS cells compared with their parental counterparts A2780 and OVCAR3, respectively (Figure 1A,B)
Western blot and densitometric analysis showed that phosphorylation levels of AKT (p-AKT) levels relative to total AKT protein (p-AKT/AKT) were significantly higher in cisplatin-resistant A2780CP20 and OVCAR3CIS cells compared with their parental counterparts
Summary
Ovarian cancer remains a significant cause of female cancer-related deaths, with approximately21,750 new cases and 13,940 deaths for 2020 in the US [1]. Ovarian cancer remains a significant cause of female cancer-related deaths, with approximately. Its high death rate is reflective of the fact that most ovarian cancer patients are diagnosed with advanced-stage disease [2]. Epithelial ovarian cancer (EOC)—the most common type of ovarian malignancies—is a complex group of diseases that, based on histopathology and molecular genetic alterations, could be divided into five main types including high-grade serous, endometrioid, clear-cell, mucinous, and low-grade serous carcinomas [3,4,5]. High-grade serous ovarian cancer (HGSOC) represents 70% of all EOCs [5]. Cancers 2020, 12, 880 initial response to first-line treatment with platinum-based combination chemotherapy, most HGSOC patients will relapse and eventually develop platinum-resistant disease with a poor overall prognosis [6].
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