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Inhibition of TPA and 12(S)‐HETE‐stimulated tumor cell adhesion by prostacyclin and its stable analogs: Rationale for their antimetastatic effects
Author(s) -
Tang D. G.,
Grossi I. M.,
Tang K. Q.,
Diglio C. A.,
Honn K. V.
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910600325
Subject(s) - prostacyclin , chemistry , endocrinology , adenosine , cell adhesion , fibronectin , medicine , cyclooxygenase , adhesion , metabolite , endothelium , pharmacology , biochemistry , extracellular matrix , biology , cell , enzyme , organic chemistry
We have investigated the regulatory role of PGI 2 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 αllb β3 integrin receptors, which mediate their adhesion to endothelium, subendothe‐lial 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 αllb β3 expression on W256 cells. PGI 2 iloprost and cicaprost inhibited both 12(S)‐HETE‐ and TPA‐enhanced adhesion to endothelium and suben‐dothelial matrix as well as αllb β3 expression on W256 cells. The mechanism responsible for the effect of PGI 2 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 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 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 PGI 2 can antagonize the lipoxygenase metabolite 12(S)‐HETE‐ and TPA‐enhanced αllb β3 expression and tumor cell adhesion via activation of adenylate cyclase and elevation of intracellular levels of cAMP. © 1995 Wiley‐Liss, Inc.