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

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

  • Gastroenterology. 2004 Jan;126(1):136-47. doi: 10.1053/j.gastro.2003.10.063.
Benjamin Chun-Yu Wong 1 Xiao Hua Jiang Marie C m Lin Shui Ping Tu Jian Tao Cui Shi Hu Jiang Wai Man Wong Man Fung Yuen Shiu Kum Lam Hsiang Fu Kung
Affiliations

Affiliation

  • 1 Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. bcywong@hku.hk
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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