Prostaglandin E₂ Synergistically Enhances Receptor Tyrosine Kinase-dependent Signaling System in Colon Cancer Cells

Cyclooxygenase (COX)-generated prostaglandin E₂ (PGE ₂) plays critical roles in colorectal carcinogenesis. Recently, we have shown that PGE₂ and transforming growth factor-α synergistically induces the expression of amphiregulin (AR) in colon cancer cells (Shao, J., Evers, B. M., and Sheng, H. (2003) Cancer Res. 63, 5218-5223). In this study, we demonstrated synergistic actions of PGE₂ and the receptor tyrosine kinase signaling system in AR expression and in tumorigenic potential of colon cancer cells. Activation of the Ras/Raf/MAPK pathway induced AR transcription in colon cancer LS-174 cells that was enhanced by PGE ₂ in a synergistic fashion. The cAMP-responsive element within the AR promoter was required for the synergistic activation of AR transcription. An Sp1 element was responsible for the basal transcription of AR and significantly enhanced the synergy between PGE₂ and the epidermal growth factor receptor (EGFR) signaling system. Furthermore, activation of both PGE ₂ and EGFR signaling pathways synergistically promoted the growth and migration of colon cancer cells. Our results suggest that COX-2/PGE ₂ may exert pro-oncogenic effects through synergistic induction of receptor tyrosine kinase-dependent signaling pathway, thus, provide a novel mechanism for the combinatorial treatment of colonic neoplasms targeting both COX-2/PGE₂ and the EGFR system that has demonstrated remarkable advantages.