Abstract
Halichondramide (HCA), a trisoxazole-containing macrolide isolated from the marine sponge Chondrosia corticata has been shown to exhibit cytotoxicity and antifungal activities. In our previous study, HCA was also found to exhibit antiproliferative activity against a variety of cancer cells. However, the precise mechanism of action of HCA in the antitumor activity remains to be elucidated. In the present study, we identified the antimetastatic activity of HCA in the highly metastatic PC3 human prostate cancer cells. HCA showed potent growth inhibitory activity of the PC3 cells with an IC50 value of 0.81 µM. Further analysis revealed that HCA suppressed the expression of a potential metastatic biomarker, phosphatase of regenerating liver-3 (PRL-3), in PC3 cells. The suppression of PRL-3 by HCA sequentially down-regulates the expression of phosphoinositide 3-kinase (PI3K) subunits p85 and p110. The antimetastatic effect of HCA was also correlated with the down-regulation of matrix metalloproteases (MMPs) and the modulation of cadherin switches N-cadherin and E-cadherin. In addition, HCA also effectively suppressed the migration and invasion of PC3 cells. These findings suggest that halichondramide might serve as a potential inhibitor of tumor cell metastasis with the modulation of PRL-3.
Highlights
Natural products have served as important sources in drug discovery and development [1]. most of the current natural product-derived therapeutic drugs originated from terrestrial plant extracts marine-based natural products are recently considered to be an important resource for procurement of new chemical entities [2]
We report for the first time that halichondramide, a trisoxazole-containing macrolide isolated from C. corticata, exhibits potent antimetastatic activity in human prostate cancer cells that is associated with the modulation of both phosphatase of regenerating liver-3 (PRL-3) and various metastasis biomarkers
To further clarify the mechanisms of action underlying the antimetastatic activity of HCA, signaling proteins that are overexpressed or inactivated in PC3 cells were examined by Western blot analysis. These analyses revealed that HCA treatment resulted in the down-regulation of the phosphatase of regenerating liver (PRL)-3 protein, which is known to be overexpressed in many metastatic cancer cell lines [15,19]; these findings are consistent with the suppression of the mRNA expression of PRL-3 by HCA
Summary
Most of the current natural product-derived therapeutic drugs originated from terrestrial plant extracts marine-based natural products are recently considered to be an important resource for procurement of new chemical entities [2]. Many compounds derived from marine sponges have exhibited anticancer activities with diverse mechanisms of action [3,4,5]. A structurally simplified macrolactone derivative of halichondrin B, which was originally isolated from the marine sponge Halichondria okadai, is an example of recently approved anticancer drug for metastatic breast cancer [6]. In our previous study, we found that oxazole-containing macrolides from the marine sponge Chondrosia corticata exhibit potential cytotoxicity and antifungal activity [7]. The mechanism underlying the antimetastatic activity of trisoxazole-containing macrolides from C. corticata has not yet been elucidated
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