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

Xiuling Li,Hsin-Hsiung Tai,Jun Li

doi:10.1371/journal.pone.0054073

Xiuling Li, Hsin-Hsiung Tai + Show 1 more

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https://doi.org/10.1371/journal.pone.0054073

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Journal: PLoS ONE	Publication Date: Jan 17, 2013
Citations: 51	License type: CC BY 4.0

Affiliation: University of Kentucky

Abstract

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 α isoform (A549-TPα). 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-TPα 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.

Highlights

There is overwhelming evidence showing that chemokines play a significant role in tumor progression, especially in cancer invasion and metastasis [1]
Induction of Monocyte Chemoattractant Protein -1 (MCP-1) Expression by Activation of thromboxane A2 receptor (TP) To examine the effects of activation of TPa on the expression of MCP-1, A549-TPa cells were treated with TP agonist I-BOP (50 nM) at different time points
The relationship between over-expression of Thromboxane synthase (TXAS) or TP, two necessary components for thromboxane A2 (TXA2) production and function, and cancer invasion and metastasis was observed in a wide range of cancers including non-small cell lung cancer (NSCLC) [36,37]

Summary

Introduction

There is overwhelming evidence showing that chemokines play a significant role in tumor progression, especially in cancer invasion and metastasis [1]. Chemokines are a superfamily of biologically active peptides which comprises about 50 members so far Among these many chemokines monocyte chemoattractant protein -1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2), a member of the CC chemokines subfamily, is of particular relevance to cancer invasion and metastasis. MCP-1 secreted by breast tumor cells recruits inflammatory monocytes that produce VEGF to promote tumor cells extravasation and lung metastasis [5,6]. CC chemokines including MCP-1 and MIP-1b were found to be associated with macrophage infiltration in human non-small cell lung cancer (NSCLC) tumors. In addition to tumor cells themselves, tumor associated stromal cells such as endothelial cells, fibroblasts and macrophages produce a significant amount of MCP-1 to increase TAM infiltration and maintain inflammation, promoting tumor progression [10,11]

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