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

Abstract

BackgroundResistance to mitoxantrone (MTX), an anthracenedione antineoplastic agent used in advanced and metastatic androgen-refractory prostate cancer (PCa), seriously limits therapeutic success.MethodsXenografts 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.ResultsA 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.ConclusionThe present data provide insight into the genetic alterations underlying MTX resistance in androgen-independent PCa and highlight potential targets to improve therapeutic outcomes.