Cyclooxygenase-2 enhances α2β1 integrin expression and cell migration via EP1 dependent signaling pathway in human chondrosarcoma cells

Ju-Fang Liu,Chin-Jung Hsu,Yi-Chin Fong,Chih-Yi Chen,Chih-Shiang Chang,Chun-Yin Huang,Wei-Hung Yang,Hsien-Te Chen,Chih-Hsin Tang,Long-Bin Jeng

doi:10.1186/1476-4598-9-43

Abstract

BackgroundCyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. Interaction of COX-2 with its specific EP receptors on the surface of cancer cells has been reported to induce cancer invasion. However, the effects of COX-2 on migration activity in human chondrosarcoma cells are mostly unknown. In this study, we examined whether COX-2 and EP interaction are involved in metastasis of human chondrosarcoma.ResultsWe found that over-expression of COX-2 or exogenous PGE2 increased the migration of human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the COX-2 which was higher than that in normal cartilage. By using pharmacological inhibitors or activators or genetic inhibition by the EP receptors, we discovered that the EP1 receptor but not other PGE receptors is involved in PGE2-mediated cell migration and α2β1 integrin expression. Furthermore, we found that human chondrosarcoma tissues expressed a higher level of EP1 receptor than normal cartilage. PGE2-mediated migration and integrin up-regulation were attenuated by phospholipase C (PLC), protein kinase C (PKC) and c-Src inhibitor. Activation of the PLCβ, PKCα, c-Src and NF-κB signaling pathway after PGE2 treatment was demonstrated, and PGE2-induced expression of integrin and migration activity were inhibited by the specific inhibitor, siRNA and mutants of PLC, PKC, c-Src and NF-κB cascades.ConclusionsOur results indicated that PGE2 enhances the migration of chondrosarcoma cells by increasing α2β1 integrin expression through the EP1/PLC/PKCα/c-Src/NF-κB signal transduction pathway.

Highlights

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis
By Western blot analysis and ELISA, respectively, we found that IPTG induced COX-2 and PGE2 expression (Fig. 1A&1B)
We demonstrated that protein kinase C (PKC) inhibitor GF109203X antagonized the PGE2-mediated potentiation of migration activity and integrin expression, suggesting that PKC activation is an obligatory event in PGE2induced a2b1 integrin expression in these cells

Summary

Introduction

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. The effects of COX-2 on migration activity in human chondrosarcoma cells are mostly unknown. We examined whether COX-2 and EP interaction are involved in metastasis of human chondrosarcoma. In the absence of an effective adjuvant therapy, this mesenchymal malignancy has a poor prognosis and it is important to explore novel and adequate remedies [2]. Since chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and metastasize distantly [2], an approach that decreases its ability to invade and metastasize may facilitate the development of effective adjuvant therapy. COX-2 is an inducible enzyme and is activated by extracellular stimuli such as growth factors and pro-inflammatory cytokines [5]

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Discussion

Conclusion