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Título: | ROCK and nuclear factor-{kappa}B–dependent activation of cyclooxygenase-2 by Rho GTPases: effects on tumor growth and therapeutic consequences |
Autor: | Aznar, Salvador CSIC ORCID; Valerón, Pilar F.; Lacal, Juan Carlos CSIC ORCID | Fecha de publicación: | jul-2003 | Editor: | American Society for Cell Biology | Citación: | Molecular Biology of the Cell 14(7): 3041-3054 (2003) | Resumen: | Rho GTPases are overexpressed in a variety of human tumors contributing to both tumor proliferation and metastasis. Recently, several studies demonstrate an essential role of transcriptional regulation in Rho GTPases-induced oncogenesis. Herein, we demonstrate that RhoA, Rac1, and Cdc42 promote the expression of cyclooxygenase-2 (COX-2) at the transcriptional level by a mechanism that is dependent on the transcription factor nuclear factor-{kappa}B (NF-{kappa}B), but not Stat3, a transcription factor required for RhoA-induced tumorigenesis. With respect to RhoA, this effect is dependent on ROCK, but not PKN. Treatment of RhoA-, Rac1-, and Cdc42-transformed epithelial cells with Sulindac and NS-398, two well-characterized nonsteroid antiinflammatory drugs (NSAIDs), results in growth inhibition as determined by cell proliferation assays. Accordingly, tumor growth of RhoA-expressing epithelial cells in syngeneic mice is strongly inhibited by NS-398 treatment. The effect of NSAIDs over RhoA-induced tumor growth is not exclusively dependent on COX-2 because DNA-binding of NF-{kappa}B is also abolished upon NSAIDs treatment, resulting in complete loss of COX-2 expression. Finally, treatment of RhoA-transformed cells with Bay11-7083, a specific NF-{kappa}B inhibitor, leads to inhibition of cell proliferation. We suggest that treatment of human tumors that overexpress Rho GTPases with NSAIDs and drugs that target NF-{kappa}B could constitute a valid antitumoral strategy. | Descripción: | 14 pages, 7 figures. | Versión del editor: | http://www.molbiolcell.org/cgi/content/full/14/7/3041 | URI: | http://hdl.handle.net/10261/24593 | ISSN: | 1059-1524 |
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