Prostaglandin E₂ stimulates the β-catenin/T cell factor-dependent transcription in colon cancer

Cyclooxygenase and its derived prostaglandin E₂ (PGE ₂) have been shown to stimulate the growth of cancer cells and promote tumor angiogenesis. Here, we show that PGE₂ activated the β-catenin/T cell factor-dependent transcription in colon cancer cells through the cAMP/protein kinase A pathway. The expression of cyclin D1 and vascular endothelial growth factor was induced by PGE₂ in LS-174T cells. Moreover, PGE₂ and mutated β-catenin stimulated the transcription of cyclin D1 and vascular endothelial growth factor in a synergistic fashion. Mechanistically, PGE₂ increased the phosphorylation of glycogen synthase kinase-3 and consequently accumulated β-catenin. In addition, PGE₂ induced the expression of T cell factor-4 transcription factor, which formed transcriptionally active complex with β-catenin. In animal experiments, administration of 16,16-dimethyl PGE₂ strongly increased the expression of cyclin D1 and vascular endothelial growth factor in APC^min/+ mouse polyps. Thus, our results provide a novel mechanism, suggesting that cyclooxygenase-2/PGE₂ may exert pro-oncogenic actions through stimulating the β-catenin/T cell factor-mediated transcription, which plays critical roles in colorectal carcinogenesis.