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Vol. 14, Issue 7, 3041-3054, July 2003

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ROCK and Nuclear Factor-B–dependent Activation of Cyclooxygenase-2 by Rho GTPases: Effects on Tumor Growth and Therapeutic Consequences

Salvador Aznar Benitah ^*, Pilar F. Valerón ^* , and Juan Carlos Lacal 

Department of Molecular and Cellular Biology of Cancer, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain

Submitted August 28, 2002; Revised March 6, 2003; Accepted March 6, 2003
Monitoring Editor: Richard Assoian

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-B (NF-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-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-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-B could constitute a valid antitumoral strategy.

Present address: Departamento de Bioquímica, Universidad de Las Palmas de Gran Canaria, Islas Canarias, Spain 28029.

Corresponding author. E-mail address: jclacal{at}iib.uam.es.

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