Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer-related death in western countries. In China, the incidence has increased, unexpectedly and sharply, for the past 20 years. Chemo-resistance, in various types of tumor including PCa, is one of the critical problems in cancer therapy. In PCa, for example, the resistance to taxanes (DTX) accounts for tumor relapse and progression resulting in skeletal metastasis and high mortality. Epithelial-mesenchymal transition (EMT) has been suggested as a key process that dominates chemo-resistance through unknown mechanisms. In the current study, we reported that CCL2 and interleukin-6 (IL-6) serve as key molecules in EMT-mediated chemo-resistance in PCa cells using previously established paclitaxel-resistant cells, DU145-TxR and PC-3-TxR. Parental DU145 and PC-3 cells were used as controls. We observed that DU145-TxR and PC-3-TxR cells produced significantly higher amount of CCL2 and IL-6 compared to their parental cells, determined by cytokine array. In addition, DU145-TxR and PC-3-TxR cells demonstrated EMT phenotypes including hall maker changes in E-cadherin and Vimentin expression and transcriptional factor (Snail, ZEB1, and Slug) alterations. These changes were reversed partially by adding neutralizing antibodies against either CCL2 or interleukin-6. Interestingly, synergistic effects were observed by adding both reagents. Finally DU145-TxR, PC-3-TxR, or their parental cells were implanted into SCID mice and the mice were given DTX (10mg/kg, biweekly) and tumor growth was monitored for 4 weeks. Both DU145-TxR and PC-3-TxR tumors grew faster than the parental tumors. Tumor tissues were collected and total RNAs were isolated. Levels of CCL2 expression in these tumors were significantly higher in DU145-TxR and PC-3-TxR tumors. IHC analysis confirmed corresponding staining of EMT markers such as E-cadherin and Vimentin expression. Together we concluded that CCL2 and IL-6 regulates EMT-mediated chemo-resistance in prostate cancer. These results are of high impact of human prostate cancer chemotherapy. Supported by U.S. Department of Defense PC061231 (J. Zhang), National Natural Sciences Foundation Key Project (81130046, J. Zhang) and National Natural Science Foundation Project (81171993, Y. Lu).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 841. doi:1538-7445.AM2012-841