Medical oncology, Hospital Clínic, Villarroel, 170, Barcelona, 08036, Spain.
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 2 models of docetaxel-resistant CRPC cell lines, and to test for the most differentially expressed genes in tumor samples from CRPC patients. 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 4 cell lines. Results showed differential expression of 243 genes (P< 0.05, Bonferroni-adjusted P-values and LogRatio>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-beta superfamily in conferring drug resistance. Changes in expression of 18 selected genes were validated by real-time quantitative RT-PCR in all 4 cell lines and tested in a set of 11 FFPE and 5 OCT tumor samples. Analysis in patients showed a noteworthy down-expression 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 CRPC patients that can circumvent such resistance to treatment.
Written by:
Marín-Aguilera M, Codony-Servat J, Kalko SG, Fernandez PL, Bermudo R, Buxo E, Ribal MJ, Gascón P, Mellado B. Are you the author?
Reference: Mol Cancer Ther. 2011 Oct 25. Epub ahead of print.
doi: 10.1158/1535-7163.MCT-11-0289
PubMed Abstract
PMID: 22027694
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