Abstract #4583: CCL25 blockade inhibits anti-apoptotic signals in prostate cancer cells and enhances cytotoxic effects of etoposide

Prostate cancer (PCa) remains the second leading cause of cancer-related deaths among men in the US. Chemotherapy is often the last option for treating hormone refractory PCa. This results in an initial response, but is nearly always followed by relapse due to chemoresistance and the indolent nature of PCa cells that have a relatively low rate of apoptosis. Therefore, better efficacy of chemotherapeutics can be achieved by combining additional agents, which can block the mechanisms responsible for this low apoptosis rate. We have previously shown functional expression of CCR9 by PCa cells. T cells primarily express CCR9 and signaling mediated by CCR9-CCL25 interactions not only induces T cell chemotaxis but the activation of anti-apoptotic pathways for T cell survival. Therefore, this study investigates CCR9-mediated anti-apoptotic signals in PCa cells in vitro and the therapeutic application of CCR9 blockade in combination with chemotherapeutic agents in vivo. PCa cell lines (PC3 and LNCaP) were treated with or without CCL25, anti-CCR9 antibody, and/or etoposide. The change in apoptosis was quantified by ImageStream analysis and CCR9-mediated activation of anti-apoptotic kinases were characterized by immunoblots. Tumor xenograft models were used to determine the in vivo efficacy of anti-CCR9 antibody or etoposide alone, or the combination of both. Tumor response to therapies was quantified by luciferase-based in vivo imaging. In the present study, we demonstrate that the interaction of CCR9 with its natural ligand (CCL25) increased the activity of anti-apoptotic proteins (i.e., PI3K, ERK1/2, AKT, and GSK-3\#946;) to promote PCa cell survival. Inhibition of CCL25-CCR9 interactions using antibody blockade enhanced the in vitro and in vivo efficacy of etoposide. These results suggest that targeting the CCL25-CCR9 axis can enhance the cytotoxic effect of etoposide. [This work was supported in part by DoD-W81XWH-06-1-0521]

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4583.