Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer

Background:Resistance to mitoxantrone (MTX), an anthracenedione antineoplastic agent used in advanced and metastatic androgen-refractory prostate cancer (PCa), seriously limits therapeutic success. Methods:Xenografts from two human PCa cell lines (VCaP and CWR22) were established in male severe combined immunodeficiency mice, and MTX was administered, with or without concurrent castration, three times a week until tumors relapsed. Microarray technology was used to screen for differentially expressed genes (DEGs) in androgen-independent, MTX-resistant PCa xenografts. Gene expression profiles of MTX-treatment xenografts and their respective parental cell lines were performed using an Agilent whole human genome oligonucleotide microarray and analyzed using Ingenuity Pathway Analysis software. Results:A total of 636 genes were differentially expressed (fold change ≥1.5; P<0.05) in MTX-resistant castration-resistant prostate cancer (CRPC) xenografts. Of these, 18 were selected to be validated and showed that most of these genes exhibited a transcriptional profile similar to that seen in the microarray (Pearson's r=0.87). Western blotting conducted with a subset of genes deregulated in MTX-resistant CRPC tumors was shown through network analysis to be involved in androgen synthesis, drug efflux, ATP synthesis, and vascularization. Conclusion:The present data provide insight into the genetic alterations underlying MTX resistance in androgen-independent PCa and highlight potential targets to improve therapeutic outcomes.