Inhibition of TPA and 12(S)-HETE-stimulated tumor cell adhesion by prostacyclin and its stable analogs: Rationale for their antimetastatic effects
✍ Scribed by D. G. Tang; I. M. Grossi; K. Q. Tang; C. A. Diglio; K. V. Honn
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- French
- Weight
- 1018 KB
- Volume
- 60
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
We have investigated the regulatory role of PGll and its stable analogs, i.e., iloprost and cicaprost, on IZ(S)-HETE-and TPA-enhanced tumor cell integrin expression and adhesion. Walker 256 carcinosarcoma cells express allbp3 integrin receptors, which mediate their adhesion to endothelium, subendothelial matrix and fibronectin. Adhesion is enhanced by treatment with exogenous IZ(S)-HETE but not IZ(R)-HETE or other lipoxygenase-derived hydroxy fatty acids, as well as by TPA. Both II(S)-HETE and TPA enhanced cullbp3 expression on W256 cells. PGlz iloprost and cicaprost inhibited both I2(S)-HETE-and TPA-enhanced adhesion to endothelium and subendothelial matrix as well as dlbp3 expression on W256 cells. The mechanism responsible for the effect of PGI, 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 PGl, effect on TPA or I2(S)-HETE-enhanced adhesion, suggesting that the PGI, effect is mediated through PKA. Dibutyryl CAMP also blocked the I2(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 PGIZ can antagonize the lipoxygenase metabolite I 2(S)-HETE-and TPA-enhanced allbf33 expression and tumor cell adhesion via activation of adenylate cyclase and elevation of intracellular levels of CAMP.