Inhibition of TPA and 12(S)-HETE-stimulated tumor cell adhesion by prostacyclin and its stable analogs: rationale for their antimetastatic effects.
We have investigated the regulatory role of PGI2 and its stable analogs, i.e., iloprost and cicaprost, on 12(S)-HETE- and TPA-enhanced tumor cell integrin expression and adhesion. Walker 256 carcinosarcoma cells express alpha IIb beta 3 integrin receptors, which mediate their adhesion to endothelium, subendothelial matrix and fibronectin. Adhesion is enhanced by treatment with exogenous 12(S)-HETE but not 12(R)-HETE or other lipoxygenase-derived hydroxy fatty acids, as well as by TPA. Both 12(S)-HETE and TPA enhanced alpha IIb beta 3 expression on W256 cells. PGI2 iloprost and cicaprost inhibited both 12(S)-HETE- and TPA-enhanced adhesion to endothelium and subendothelial matrix as well as alpha IIb beta 3 expression on W256 cells. The mechanism responsible for the effect of PGI2 was explored. Prostacyclin treatment of W256 cells resulted in an enhanced production of cAMP in a time- and dose-dependent manner. Pre-treatment of tumor cells with increasing concentrations of adenosine resulted in a dose-dependent decrease in the PGI2 effect on TPA or 12(S)-HETE-enhanced adhesion, suggesting that the PGI2 effect is mediated through PKA. Dibutyryl cAMP also blocked the 12(S)-HETE- or TPA-enhanced adhesion, and adenosine pre-treatment did not result in an inhibition of the dibutyryl cAMP effect. Collectively, our results suggest that the cyclooxygenase metabolite PGI2 can antagonize the lipoxygenase metabolite 12(S)-HETE- and TPA-enhanced alpha IIb beta 3 expression and tumor cell adhesion via activation of adenylate cyclase and elevation of intracellular levels of cAMP.
Tang
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Department of Radiation Oncology, Wayne State University, Detroit, MI 48202.
Grossi
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Tang
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D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents; D002448:Cell Adhesion / Q000187:drug effects*; D000242:Cyclic AMP / Q000502:physiology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors*; D016285:Iloprost / Q000494:pharmacology*; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006893:Hydroxyeicosatetraenoic Acids; D016023:Integrins; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D011464:Epoprostenol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D016285:Iloprost; C043867:cicaprost; D013755:Tetradecanoylphorbol Acetate