Antimetastatic activity of halichondramide for human prostate cancer cells via modulation of PRL-3 signaling

Halichondramide, a trisoxazole-containing macrolide, was isolated from the marine sponge Chondrosia corticata. Halichondramide (HCA) has been shown to exhibit cytotoxicity and antifungal activity. Recent our study exhibited the growth inhibitory activity against a variety of cancer cells. However, the precise mechanism of action of HCA in the antitumor activity remains to be identified. In the present study, the antimetastatic activity of HCA was elucidated in human prostate cancer cells. HCA was found to exhibit the potent growth inhibitory activity of the highly metastatic PC3 prostate cancer cells with an IC₅₀ value of 0.81µM. Additional mechanism of action studies revealed that HCA suppressed the expression of a potential metastatic biomarker phosphatase of regenerating liver-3 (PRL-3) in the PC3 cells. The suppression of PRL-3 by HCA sequentially down-regulates the expression of p85 and p110. The antimetastatic effect of HCA was also correlated with the down-regulation of matrix metalloproteases (MMPs) and N-cadherin, and with the up-regulation of E-cadherin in PC3 cells. HCA also inhibited the migration and invasion of PC3 cells in a dose-dependent manner. These findings suggest that the antimetastatic activity of halichondramide is associated with the inhibition of PRL-3 activity in PC3 cells and thus might be served as a potential candidate for development of cancer chemotherapeutic agents from marine organisms.