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Inhibition of Activator Protein 1 Activation, Vascular Endothelial Growth Factor, and Cyclooxygenase-2 Expression by 15-Deoxy-^12,14-Prostaglandin J₂ in Colon Carcinoma Cells: Evidence for a Redox-Sensitive Peroxisome Proliferator-Activated Receptor--Independent Mechanism

Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain

Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are significantly associated with tumor growth and metastasis. Here we show that phorbol ester-mediated induction of VEGF and COX-2 expression in colon carcinoma cells is inhibited by 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂). This cyclopentenone was able to inhibit activator protein1 (AP-1)-dependent transcriptional induction of COX-2 and VEGF promoters induced by phorbol 12-myristate 13-acetate (PMA) or c-Jun overexpression. 15d-PGJ₂ interfered with at least two steps within the signaling pathway leading to AP-1 activation. First, 15d-PGJ₂ impaired AP-1 binding to a consensus DNA sequence. Second, 15d-PGJ₂ selectively inhibited c-Jun NH₂ terminal kinase (JNK) but not extracellular signal-regulated kinase or p38 mitogen-activated protein kinase activation induced by PMA. This led to a decreased ability of JNK to phosphorylate c-Jun and to activate its transactivating activity. Inhibition of AP-1 activation and COX-2 or VEGF transcriptional induction by this cyclopentenone was found to be independent of peroxisome proliferator-activated receptor- (PPAR) because it was not affected by either expression of a dominant negative form of PPAR or the use of a PPAR antagonist. In contrast, we have found that the effects of 15d-PGJ₂ on AP-1 activation may occur through its ability to induce intracellular oxidative stress. The antioxidant N-acetylcysteine significantly reversed the inhibition by 15d-PGJ₂ of AP-1 activity and COX-2 or VEGF transcriptional induction. Together, these findings provide new insight into the antitumoral properties of 15d-PGJ₂ through the inhibition of the induction of AP-1-dependent genes involved in tumor progression, such as COX-2 and VEGF.

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