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Submitted on July 19, 2002
Accepted on January 17, 2003
1 Department of Biochemistry and Experimental Endocrinology, University of Crete, School of Medicine, GR-71110 Heraklion, Greece
* To whom correspondence should be addressed. E-mail: cstourn{at}med.uoc.gr.
The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors, which modify the actin cytoskeleton and increase the secretion of PSA within minutes. Membrane steroid receptors are, indeed, a newly identified element of steroid action, which are different from the classical intracellular sites. In the present work, using a non-permeable analog of testosterone (testosterone-BSA), we investigated the signaling pathway that is triggered by the membrane testosterone receptors' activation and leads to actin cytoskeleton reorganization. We report that exposure of cells to testosterone-BSA resulted in phosphorylation of focal adhesion kinase (FAK), the association of FAK with the phosphatidylinositol-3 (PI-3) kinase and the subsequent activation of the latter as well as in activation of the small GTPases Cdc42/Rac1. Pre-treatment of cells with the specific PI-3 kinase inhibitor wortmannin abolished both, the activation of the small GTPases and the alterations of actin cytoskeleton, while it did not affect the phosphorylation of FAK. These findings indicate that PI-3 kinase is activated downstream of FAK and upstream of Cdc42/Rac1 which subsequently regulate the actin organization. Moreover, wortmannin diminished the secretion of PSA implying that the signaling events described above are responsible for the testosterone-BSA-induced PSA secretion. Our results are discussed under the prism of a possible implication of these membrane receptors in prostate cancer chemotherapy.
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