Iloprost, a prostacyclin analog, inhibits the invasion of ovarian cancer cells by downregulating matrix metallopeptidase-2 (MMP-2) through the IP-dependent pathway

Recent studies have shown that a bioactive lipid prostacyclin (PGI₂) plays a role in various cancers, including lung cancer. However, the specific function of PGI₂ in ovarian cancer progression has not been determined. This study investigated the effects of PGI₂ on cell growth, migration, and invasion in ovarian cancer cells using iloprost, a stable PGI₂ analog. Iloprost significantly inhibited migration and invasion, but not cell growth, in a dose-dependent manner in human ovarian cancer cells (A2780 and SKOV3). Interestingly, the cell surface Gs protein-coupled PGI₂ receptor IP was enhanced in human ovarian cancer cells. The inhibitory effect of iloprost on migration and invasion was entirely reversed by an IP antagonist (CAY10449) and IP siRNA, whereas the knockdown of peroxisome proliferator-activated receptor δ (PPARδ), a nuclear receptor of PGI₂, did not rescue the effect of iloprost. Additionally, iloprost markedly decreased the expression of matrix metallopeptidase-2 and -9 (MMP-2 and MMP-9), which may be induced in the process of ovarian cancer metastasis. IP siRNA inhibited iloprost-reduced MMP-2 expression but not MMP-9 expression. Moreover, inhibition of protein kinase A (PKA) and overexpression of Akt and p38 rescued the inhibition of invasion and the reduction of MMP-2 expression by iloprost. Furthermore, iloprost-induced activation of PKA was associated with PKA-mediated Akt and p38 inactivation in ovarian cancer cells. Taken together, these results demonstrate that iloprost inhibits ovarian cancer cell invasion by downregulating MMP-2 expression via the IP-mediated PKA pathway. This study is the first to reveal a novel role for iloprost and to clarify its underlying mechanism in human ovarian cancer cells.