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

Benjamin Chun-Yu Wong1, Xiao Hua Jiang, Marie C m Lin

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

Gastroenterology
|December 31, 2003
PubMed
Abstract

Insights

The COX-2 inhibitor SC-236 suppresses gastric cancer growth by inhibiting the c-Jun-N-terminal kinase (JNK) and activator protein-1 (AP-1) signaling pathway. This targeted inhibition of JNK activation offers potential therapeutic benefits for gastric cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aspirin's antitumor effects involve blocking activator protein-1 (AP-1) activation.
  • Cyclooxygenase-2 (COX-2) specific inhibitors offer a targeted approach to cancer therapy.

Purpose of the Study:

  • To investigate how the COX-2 inhibitor SC-236 mediates antitumor effects by modulating the AP-1 signaling pathway.
  • To determine the role of JNK in SC-236's anticancer activity.

Main Methods:

  • AP-1 transcriptional and DNA-binding activity assessed via luciferase reporter and gel shift assays.
  • Mitogen-activated protein kinase (MAPK) activation analyzed by Western blot and kinase assays.
  • JNK expression suppressed using antisense oligonucleotides.

Main Results:

  • SC-236 inhibited PMA-induced cell transformation, anchorage-independent growth, and AP-1 activation in gastric cancer cells.
  • SC-236 dose-dependently reduced JNK phosphorylation and activity, independent of COX-prostaglandin synthesis.
  • Suppression of JNK activity reversed SC-236's effects on AP-1 and gastric cancer cell growth.

Conclusions:

  • Inhibition of JNK-c-Jun/AP-1 activation contributes to the antitumor effect of COX-2 inhibitors.
  • Targeting JNK activation presents a potential therapeutic strategy for gastric cancer.

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