Activation of Thromboxane A2 Receptor (TP) Increases the Expression of Monocyte Chemoattractant Protein 1 (MCP 1)/Chemokine (C C motif) Ligand 2 (CCL2) and Recruits Macrophages to Promote Invasion of Lung Cancer Cells
Thromboxane synthase (TXAS) and thromboxane A2 receptor (TP) two critical components for thromboxane A2 (TXA2) signaling, have been suggested to be involved in cancer invasion and metastasis. However, the mechanisms by which TXA2 promotes these processes are still unclear. Here we show that TXA2 mimetic, I BOP, induced monocyte chemoattractant protein 1(MCP 1)/chemokine (C C motif) ligand 2 (CCL2) expression at both mRNA and protein levels in human lung adenocarcinoma A549 cells stably over expressing TP receptor a isoform (A549 TPa) The induction of MCP 1 was also found in other lung cancer cells H157 and H460 that express relatively high levels of endogenous TP. Using specific inhibitors of several signaling molecules and promoter/luciferase assay, we identified that transcription factor SP1 mediates I BOP induced MCP 1 expression. Furthermore, supernatants from I BOP treated A549 TPa cells enhanced MCP 1 dependent migration of RAW 264.7 macrophages. Moreover, co culture of A549 cells with RAW 264.7 macrophages induced expression of MMPs, VEGF and MCP 1 genes, and increased the invasive potential in A549 cells. These findings suggest that TXA2 may stimulate invasion of cancer cells through MCP 1 mediated macrophage recruitment.
PloS one