MP61-19 A NOVEL STRATEGY TO OPTIMISE TREATMENT OF DOCETAXEL-RESISTANT PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: LK-1 is a transcriptional factor whose phosphorylation is necessary for c-fos proto-oncogene activation. However, little is known about biological significance of ELK1 in prostate cancer. In addition, silodosin, a selective a1-adrenergic blocker used for the symptomatic treatment of benign prostatic hyperplasia, has been shown to decrease ELK-1 expression in human prostate smooth muscle cells. In this study, we aim to investigate the functions of ELK-1 in prostate cancer growth and the efficacy of silodosin, in combination with chemotherapeutic drugs, in cell proliferation. METHODS: We first immunohistochemically determined the levels of phospho-ELK-1 (pELK-1) expression in radical prostatectomy specimens. We then assessed the effects of ELK-1 knockdown via short hairpin RNA on cell proliferation, migration, and invasion as well as those of silodosin on ELK-1 expression/activity in prostate cancer lines and their viability. RESULTS: Immunohistochemistry showed that the levels of pELK-1 expression were significantly higher in carcinoma (positivity & score, P<0.001) or high-grade prostatic intraepithelial neoplasia (HGPIN) (positivity & score, P<0.001) than in benign as well as in carcinoma than in HGPIN (positivity, P1⁄40.330; score, P1⁄40.002). Although none of the 7 patients with pELK-1-negative carcinoma had biochemical recurrence after radical prostatectomy, Kaplan-Meier and log-rank tests revealed no significant correlations of pELK-1 levels with patient outcomes. In PC3 and DU145 cells expressing ELK-1 (mRNA, protein), ELK-1 silencing resulted in decreases in the expression of cfos, a downstream target of ELK-1 signals, as well as in cell viability/ colony formation, cell migration/invasion, and the expression of matrix metalloproteinase (MMP)-2 and MMP-9. In these cells, silodosin reduced the expression of a1-adrenergic receptor, ELK-1, and c-fos as well as the transcriptional activity of ELK-1. However, silodosin alone (up to 10 mM) only marginally inhibited PC3/DU145 cell growth. Interestingly, silodosin treatment in the prostate cancer lines increased sensitivity to gemcitabine, but not to cisplatin or docetaxel. CONCLUSIONS: ELK-1 is likely activated in prostate cancer cells. Our results also suggest that ELK-1 plays an important role in prostate cancer progression. Thus, ELK-1 inhibition has the potential of being a therapeutic approach for prostate cancer. Furthermore, silodosin that inactivates ELK-1 in prostate cancer cells enhances the cytotoxic activity of gemcitabine.