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 docetaxel-resistant 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-β 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.
Highlights
Prostate cancer is the second most common cancer among men worldwide [1]
DU-145 and DU-145R cell lines were cultured in RPMI-1640 medium (Invitrogen), and PC-3 and PC-3R in F-12K nutrient mixture medium (Invitrogen), both supplemented with 10% FBS
Expressed genes in resistant cells Initially, unsupervised clustering analysis of microarrays was carried out using the probe sets that varied most throughout the whole experiment, and this exploration revealed a good segregation of the arrays in their respective classes on the basis of expression values
Summary
Prostate cancer is the second most common cancer among men worldwide [1]. 85% of newly diagnosed prostate cancer cases are localized to the prostate, whereas the remainder are invasive or metastatic disease [2]. Patients with metastatic prostate cancer respond initially to antiandrogen therapy. Tumors eventually progress and transform themselves into castration-resistant prostate cancer (CRPC). Docetaxel improves survival of patients with metastatic CRPC and is considered a standard first-line therapy in such cases [3; 4].
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