Endogenous PGE2 induces MCP-1 expression via EP4/p38 MAPK signaling in melanoma

Abstract

It has been demonstrated that cyclooxygenase-2 (COX-2) is expressed in melanoma tissues and prostaglandin E2 (PGE2) is produced by melanoma cells in vitro. However, the roles of COX-2/PGE2 in melanoma are largely unknown. In the present study, we set out to analyze the correlation of endogenous PGE2 with the expression of macrophage chemoattractant protein-1 (MCP-1) and to identify the signaling pathway involved. It was found that MCP-1 mRNA was heterogeneously expressed in 18 melanoma tissue specimens, and the levels of MCP-1 mRNA were positively correlated with those of COX-2 mRNA. Inhibition of endogenous PGE2 production by a COX-2 inhibitor, COX-2 siRNA or an NFκB inhibitor suppressed MCP-1 expression, whereas treatment with TNF-α (to stimulate endogenous PGE2 production) or exogenous PGE2 enhanced MCP-1 expression in melanoma cells. Both the EP4 antagonist and the p38 MAPK inhibitor reduced MCP-1 production in melanoma cells, and abrogated the increased MCP-1 secretion induced by TNF-α or exogenous PGE2. Conditioned medium from melanoma cells promoted macrophage migration, which was blocked by inhibitors of the PGE2/EP4/p38 MAPK signaling pathway. These results indicate that endogenous PGE2 induces MCP-1 expression via EP4/p38 MAPK signaling in an autocrinal manner in melanoma, and melanoma cell-derived PGE2 may be involved in macrophage recruitment in the melanoma microenvironment.