Inhibition of Activator Protein 1 Activation, Vascular Endothelial Growth Factor, and Cyclooxygenase-2 Expression by 15-Deoxy-Δ12,14-Prostaglandin J2 in Colon Carcinoma Cells: Evidence for a Redox-Sensitive Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanism
Open Access
- 1 August 2004
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 64 (15) , 5162-5171
- https://doi.org/10.1158/0008-5472.can-04-0849
Abstract
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-Δ12,14-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-γ (PPARγ) because it was not affected by either expression of a dominant negative form of PPARγ or the use of a PPARγ 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.Keywords
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