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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

Benjamin Chun-Yu Wong, 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

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

PMID: 14699495

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP170569865	SC-236		170569-86-5	Price

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