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Abstract
BackgroundCisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition.MethodsTo model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis.ResultsPromoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI50 values (i.e., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells.ConclusionSelective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.
Highlights
Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer
Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response
Establishment of a cell culture model of acquired ovarian cancer platinum resistance To establish a model for the development of ovarian tumor cisplatin resistance, we exposed clonally derived, platinum-sensitive A2780 ovarian cancer cells [46] to incrementally increasing doses of cisplatin, with drug sensitivity assessed by MTT cell proliferation assays
Summary
Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer Resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. The precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition. Transcriptional silencing of distinct DNA repair and apoptosisassociated genes by hypermethylation of promoter "CpG islands" (CGIs), CG-rich DNA regions typically unmethylated in normal cells [15], has been associated with platinum drug resistance in numerous cancers, including ovarian [9,16,17,18,19,20,21]. No previous global studies of the accumulation of DNA methylation aberrations, during the gradual acquisition of chemoresistance, or their likely impact on specific biological signaling pathways, have been reported in cancer
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