Identification of Docetaxel Resistance Genes in Castration-Resistant Prostate Cancer

Abstract

Docetaxel-based chemotherapy is the standard first-line therapy in metastatic castration-resistant prostate cancer (CRPC). However, most patients eventually develop resistance to this treatment. In this study, we aimed to identify key molecular genes and networks associated with docetaxel resistance in two models of docetaxelresistant CRPC cell lines and to test for the most differentially expressed genes in tumor samples from patients with CRPC. DU-145 and PC-3 cells were converted to docetaxel-resistant cells, DU-145R and PC-3R, respectively. Whole-genome arrays were used to compare global gene expression between these four cell lines. Results showed differential expression of 243 genes (P < 0.05, Bonferroni-adjusted P values and log ratio > 1.2) that were common to DU-145R and PC-3R cells. These genes were involved in cell processes like growth, development, death, proliferation, movement, and gene expression. Genes and networks commonly deregulated in both DU-145R and PC-3R cells were studied by Ingenuity Pathways Analysis. Exposing parental cells to TGFB1 increased their survival in the presence of docetaxel, suggesting a role of the TGF-b superfamily in conferring drug resistance. Changes in expression of 18 selected genes were validated by real-time quantitative reverse transcriptase PCR in all four cell lines and tested in a set of 11 FFPE and five optimal cutting temperature tumor samples. Analysis in patients showed a noteworthy downexpression of CDH1 and IFIH1, among others, in docetaxel-resistant tumors. This exploratory analysis provides information about potential gene and network involvement in docetaxel resistance in CRPC. Further clinical validation of these results is needed to develop targeted therapies in patients with CRPC that can circumvent such resistance to treatment.

New and Old Genes Associated with Topotecan Resistance Development in Ovarian Cancer Cell Lines

“…So far, IFIH1 expression has been described mainly as a cytosolic receptor responsible for double-strand RNA recognition and antiviral response (29,30). Marín-Aguilera et al reported on decreased expression of IFIH1 gene in castration-resistant prostate cancers resistant to Docetaxel (DOC) and in prostate cancer cell lines resistant to DOC (42). In contrast, we observed an up-regulation of this gene in TOP-resistant ovarian cancer cell lines.…”

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…In previous work, we identified 243 genes with differential expression in CRPC docetaxel-sensitive versus docetaxel-resistant cell lines (16). In the present study, 73 genes from that study together with 20 genes from the literature were tested in tumor specimens of patients with high-risk localized prostate cancer included in a clinical trial of neoadjuvant hormone chemotherapy (17), and compared with nontreated specimens with similar clinical characteristics.…”

“…A set of 73 target genes was selected for their relative expression in docetaxel-resistant cells (DU-145R and PC-3R) versus parental cells (DU-145 and PC-3; ref. 16) using DAVID (21) and Ingenuity Pathway Analysis software (http://www.ingenuity.com). Twenty genes highlighted in the literature as potential targets of docetaxel resistance were also selected.…”

Prognostic and Predictive Biomarkers for Castration Resistant Prostate Cancer

“…By inducing docetaxel-resistant DU-145 PC cells in culture, Marín-Aguilera compared global gene expression between docetaxel-sensitive and docetaxelresistant cell lines and found that exposing parental cells to TGF-b1 increased their survival in the presence of docetaxel. The result suggested a role of the TGF-b superfamily in conferring docetaxel resistance (Marín-Aguilera et al 2012). It was also reported that men with prostate cancer carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with others carrying at least one copy of the CYP1B1*1 allele (Sissung et al 2008).…”