FTY720, a fungus metabolite, inhibits invasion ability of androgen independent prostate cancer cells through inactivation of RhoA-GTPase

Abstract

The failure of controlling androgen-independent and metastatic prostate cancer growth is the main cause of death in prostate cancer patients. In this study, we have demonstrated a novel anticancer agent, FTY720, a fungus metabolite, in the suppression of metastatic ability of androgen independent prostate cancer cells. First, using colony forming assay, we found that FTY720 treatment led to decreased colony forming ability of androgen-independent prostate cancer cell lines DU145 and PC3, indicating its negative role on cancer cell survival. In addition, treatment with relatively low dose of FTY720 (i.e. Inhibitory Concentration of 50% cell survival) resulted in suppression of prostate cancer cell migration and invasion abilities demonstrated by Wound closure assay, 3-D collagen gel invasion assays and stress fiber staining. Furthermore, we found that the inhibitory effect of FTY720 on prostate cancer invasion was associated with down-regulation of GTP-bound active form of RhoA. Transfection of a dominant-active RhoA vector in DU145 and PC3 cells conferred resistance to FTY720-induced suppression of cell motility. These results indicate that FTY720 may be a potential effective agent against androgen independent prostate cancer. Since activation of RhoA-GTPase is associated with metastasis in many types of malignancies, our results not only suggest a new agent for the treatment of advanced prostate cancer, but also implicate a possible novel anti-cancer drug especially against metastatic cancers.