Abstract
PurposeThe present study is to discover a new genes associated with drug resistance development in ovarian cancer.MethodsWe used microarray analysis to determine alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines. Immunohistochemistry assay was used to determine protein expression in ovarian cancer patients.ResultsWe observed alterations in the expression of 22 genes that were common to all three cell lines that were resistant to the same cytostatic drug. The level of expression of 13 genes was upregulated and that of nine genes was downregulated. In the CisPt-resistant cell line, we observed downregulated expression of ABCC6, BST2, ERAP2 and MCTP1; in the Pac-resistant cell line, we observe upregulated expression of ABCB1, EPHA7 and RUNDC3B and downregulated expression of LIPG, MCTP1, NSBP1, PCDH9, PTPRK and SEMA3A. The expression levels of three genes, ABCB1, ABCB4 and IFI16, were upregulated in the Dox-resistant cell lines. In the Top-resistant cell lines, we observed increased expression levels of ABCG2, HERC5, IFIH1, MYOT, S100A3, SAMD4A, SPP1 and TGFBI and decreased expression levels of MCTP1 and PTPRK. The expression of EPHA7, IFI16, SPP1 and TGFBI was confirmed at protein level in analyzed ovarian cancer patients..ConclusionsThe expression profiles of the investigated cell lines indicated that new candidate genes are related to the development of resistance to the cytostatic drugs that are used in first- and second-line chemotherapy of ovarian cancer.
Highlights
Ovarian cancer is one of the most lethal gynecological malignancies
The expression of EPHA7, IFI16, SPP1 and TGFBI was confirmed at protein level in analyzed ovarian cancer patients
The expression profiles of the investigated cell lines indicated that new candidate genes are related to the development of resistance to the cytostatic drugs that are used in first- and second-line chemotherapy of ovarian cancer
Summary
Ovarian cancer is one of the most lethal gynecological malignancies. Most patients are diagnosed with an advanced disease and have a poor prognosis [1]. During treatment, ovarian cancer cells may develop drug resistance, causing further treatments to be ineffective in most cases [2]. The most significant mechanism underlying the resistance to cytostatic drugs is their active removal from cancer cells by drug transporters of the ABC family [3]. These transporters pump cytostatic drugs from cancer cells using energy derived from ATP hydrolysis [4]. Other mechanisms underlying cytostatic-drug resistance include the following: inactivating the drugs using detoxification enzymes, inactivating the drugs through metallothionein or glutathione binding, repairing damaged DNA, developing point mutations in the genes that encode proteins that bind cytostatic drugs, and increasing the activity of anti-apoptotic or pro-survival pathways as well as disrupting apoptotic signaling pathways [7]
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