Cyclooxygenase (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.

We 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 alpha2beta1 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 PLC, PKC, c−Src and NF−kappaB 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−kappaB cascades.

Our results indicated that PGE2 enhances the migration of chondrosarcoma cells by increasing alpha2beta1 integrin expression through the EP1/PLC/PKCalpha/c−Src/NF−kappaB signal transduction pathway.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.