Expression of cyclooxygenase-2 is regulated by glycogen synthase kinase-3beta in gastric cancer cells.

Abstract

Cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in gastric cancer patients, and its inhibition suppresses gastric tumorigenesis in experimental animal models. The mechanism that leads to COX-2 overexpression in this tumor type is unknown. We have now shown that inhibition of phosphatidylinositol 3-kinase by LY294002 suppresses both basal and phorbol myristate acetate-induced COX-2 expression in TMK-1 and MKN-28 gastric cancer cells. Furthermore, inhibition of glycogen synthase kinase-3beta (GSK-3beta) by SB415286 induced expression of COX-2 mRNA and protein as well as the enzyme activity in the gastric cancer cells. The effect of SB415286 was confirmed by the use of two additional GSK-3beta inhibitors, lithium chloride and SB216763. SB415286 had a modest 1.6-fold stimulatory effect on a 2-kb COX-2 promoter reporter construct, but more importantly, it was shown to block the decay of COX-2 mRNA. In contrast to modulation of phosphatidylinositol 3-kinase/Akt/GSK-3beta pathway, inhibitors of mitogen-activated protein kinases (MEK 1/2, p38, JNK) or the mammalian target of rapamycin did not alter COX-2 expression in gastric cancer cells. Our data show that inhibition of GSK-3beta stimulates COX-2 expression in gastric cancer cells, which seems to be primarily facilitated via an increase in mRNA stability and to a lesser extent through enhanced transcription.

• Authors: Alexandra Thiel, Mira Heinonen, Johanna Rintahaka, Tuija Hallikainen, Annabrita Hemmes, Dan A Dixon, Caj Haglund, Ari Ristimäki
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 8 Pg. 4564-9 (Feb 24 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16371352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
• Aminophenols
• Chromones
• Enzyme Inhibitors
• Indoles
• Maleimides
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger
• SB 216763
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• RNA
• Cyclooxygenase 2
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Lithium Chloride
• Dinoprostone
• Tetradecanoylphorbol Acetate

Topics

• Aminophenols (pharmacology)
• Blotting, Northern
• Blotting, Western
• Cell Line, Tumor
• Chromones (pharmacology)
• Cyclooxygenase 2 (biosynthesis)
• Dinoprostone (metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Indoles (pharmacology)
• Lithium Chloride (pharmacology)
• Maleimides (pharmacology)
• Models, Biological
• Models, Statistical
• Morpholines (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA (metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Stomach Neoplasms (metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)
• Time Factors
• Transfection