INHIBITION OF TPA AND 12(S)-HETE-STIMULATED TUMOR-CELL ADHESION BY PROSTACYCLIN AND ITS STABLE ANALOGS - RATIONALE FOR THEIR ANTIMETASTATICEFFECTS

We have investigated the regulatory role of PGI(2) and its stable anal ogs, i.e., iloprost and cicaprost, on 12(S)-HETE- and TPA-enhanced tum or cell integrin expression and adhesion. Walker 256 carcinosarcoma ce lls express alpha 11b beta 3 integrin receptors, which mediate their a dhesion to endothelium, subendothelial matrix and fibronectin. Adhesio n is enhanced by treatment with exogenous 12(S)-HETE but not 12(R)-HET E or other lipoxygenase-derived hydroxy fatty acids, as well as by TPA . Both 12(S)-HETE and TPA enhanced alpha 11b beta 3 expression on W256 cells. PGI(2) iloprost and cicaprost inhibited both IZ(S)-HETE- and T PA-enhanced adhesion to endothelium and subendothelial matrix as well as alpha 11b beta 3 expression on W256 cells. The mechanism responsibl e for the effect of PGI(2) was explored. Prostacyclin treatment of W25 6 cells resulted in an enhanced production of cAMP in a time- and dose -dependent manner. Pre-treatment of tumor cells with increasing concen trations of adenosine resulted in a dose-dependent decrease in the PGI (2) effect on TPA or 12(S)-HETE-enhanced adhesion, suggesting that the PGI(2) effect is mediated through PKA. Dibutyryl cAMP also blocked th e 12(S)-HETE- or TPA-enhanced adhesion, and adenosine pre-treatment di d not result in an inhibition of the dibutyryl cAMP effect. Collective ly, our results suggest that the cyclooxygenase metabolite PGI(2) can antagonize the lipoxygenase metabolite 12(S)-HETE- and TPA-enhanced al pha 11b beta 3 expression and tumor cell adhesion via activation of ad enylate cyclase and elevation of intracellular levels of cAMP. (C) 199 5 Wiley-Liss, Inc.