Docetaxel is a first-line anticancer drug widely used in the treatment of advanced prostate cancer. However, its therapeutic efficacy is limited by its side effects and the development of chemoresistance by the tumor. Using a gene differential expression microarray, we identified 449 genes differentially expressed in docetaxel-resistant DU145 and PC3 cell lines as compared to docetaxel-sensitive controls. Moreover, western blotting and immunohistochemistry revealed altered expression of S100A4, ACKR3 and CDH1in clinical tumor samples. Cytoscape software was used to investigate the relationship between critical proteins and their signaling transduction networks. Functional and pathway enrichment analyses revealed that these signaling pathways were closely related to cellular proliferation, cell adhesion, cell migration and metastasis. In addition, ACKR3 knockout using the crispr/cas9 method andS100A4knockdownusing targeted shRNA exerted additive effects suppressing cancer cell proliferation and migration. This exploratory analysis provides information about potential candidate genes. It also provides new insight into the molecular mechanism underlying docetaxel-resistance in androgen-independent prostate cancer and highlights potential targets to improve therapeutic outcomes.