Abstract 772: CCL2 regulates EMT-mediated chemo-resistance in prostate cancer

Abstract

Abstract Prostate cancer 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 prostate cancer, is one of the critical problems in cancer therapy. In prostate cancer, for example, the resistance to taxanes (paclitaxel or docetaxel, 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 serves as key molecules in EMT-mediated chemo-resistance in prostate cancer cells using paclitaxel-resistant cells, DU145-TxR, PC-3-TxR and C4-2B-TxR. Parental prostate cancer cells were used as controls. We observed that DU145-TxR, PC-3-TxR and C4-2B-TxR cells produced significantly higher amount of CCL2 compared to their parental cells, determined by cytokine array. In addition, DU145-TxR, PC-3-TxR and C4-2B-TxR cells demonstrated EMT phenotypes including hall maker changes in E-cadherin and Vimentin expression and transcriptional factor (Snail, ZEB1, and Slug) alterations, examined by western blot. These changes were reversed partially by adding neutralizing antibodies against CCL2. Finally DU145-TxR, PC-3-TxR, and C4-2B-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, PC-3-TxR and C4-2B-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, PC-3-TxR and C4-2B-TxR tumors. IHC analysis confirmed corresponding staining of EMT markers such as E-cadherin and Vimentin expression. Together we concluded that CCL2 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; NSF key project 81130046; NSF projects 81171993 and 81272415. Citation Format: Wenchu Wang, Yi Lu, Xiaolin Zhou, Atsushi Mizokami, Evan Keller, Jian Zhang. CCL2 regulates EMT-mediated chemo-resistance in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 772. doi:10.1158/1538-7445.AM2014-772