Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase.

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Wong BC, Jiang XH, Lin MC, Tu SP, Cui JT, Jiang SH, Wong WM, Yuen MF, Lam SK, Kung HF

Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase.

Gastroenterology. 2004 Jan;126(1):136-47.

PubMed ID
14699495 [ View in PubMed
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Abstract

BACKGROUND AND AIMS: Aspirin exerts antitumor effect partly through blocking tumor promoter-induced activator protein-1 (AP-1) activation. The aim of this study is to determine how specific COX-2 inhibitor SC-236 mediates antitumor effect by modulation of AP-1-signaling pathway. METHODS: AP-1 transcriptional activity and DNA-binding activity were detected by luciferase reporter assay and gel shift assay, separately. Mitogen-activated protein kinase (MAPK) activation was determined by Western blot and in vitro kinase assay. Antisense oligonucleotide against c-Jun-N-terminal kinase (JNK) was used to suppress JNK expression. RESULTS: We showed that SC-236 inhibited 12-O-tetradecanoylphorbol-13-acetate (PMA)-induced cell transformation in a dose-dependent manner in JB6 cells. At a dose range (12.5-50 micromol/L) that inhibited cell transformation, SC-236 also inhibited anchorage-independent cell growth and AP-1-activation in 3 gastric cancer cells, independent of COX-prostaglandin synthesis. SC-236 down-regulated c-Jun-NH2-terminal kinase phosphorylation and activity. Suppression of JNK activity reversed the inhibitory effect on AP-1 activity by SC-236 and suppressed gastric cancer cell growth, indicating that the inhibitory effect of SC-236 on AP-1 activation and cell growth was through interaction with JNK. CONCLUSIONS: The inhibitory effect on JNK-c-Jun/AP-1 activation contributes to the antitumor effect of COX-2-specific inhibitor, and inhibition of JNK activation may have a therapeutic benefit against gastric cancer.

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