AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma

Chin-Jung Hsu,Min-Huan Wu,Chin-Yuan Chen,Chun-Hao Tsai,Horng-Chaung Hsu,Chih-Hsin Tang

doi:10.1186/1478-811x-11-68

Abstract

Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein-1α, is a cytokine involved in inflammation and activation of polymorphonuclear leukocytes. CCL3 has been detected in infiltrating cells and tumor cells. Chondrosarcoma is a highly malignant tumor that causes distant metastasis. However, the effect of CCL3 on human chondrosarcoma metastasis is still unknown. Here, we found that CCL3 increased cellular migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. Pre-treatment of cells with the MMP-2 inhibitor or transfection with MMP-2 specific siRNA abolished CCL3-induced cell migration. CCL3 has been reported to exert its effects through activation of its specific receptor, CC chemokine receptor 5 (CCR5). The CCR5 and AMP-activated protein kinase (AMPK) inhibitor or siRNA also attenuated CCL3-upregulated cell motility and MMP-2 expression. CCL3-induced expression of MMP-2 and migration were also inhibited by specific inhibitors, and inactive mutants of AMPK, p38 mitogen activated protein kinase (p38 or p38-MAPK), and nuclear factor κB (NF-κB) cascades. On the other hand, CCL3 treatment demonstrably activated AMPK, p38, and NF-κB signaling pathways. Furthermore, the expression levels of CCL3, CCR5, and MMP-2 were correlated in human chondrosarcoma specimens. Taken together, our results indicate that CCL3 enhances the migratory ability of human chondrosarcoma cells by increasing MMP-2 expression via the CCR5, AMPK, p38, and NF-κB pathways.

Highlights

Chondrosarcomas are the third most common bone tumors, after myelomas and osteosarcomas
Correlation of CCL3, chemokine receptor 5 (CCR5), and matrix metalloproteinase (MMP)-2 expression in human chondrosarcoma specimens Previous study suggest that CCL3 is overexpressed in many cancer types [26]
These results indicate that CCL3, CCR5, and MMP-2 expression are correlated in human chondrosarcoma specimens

Summary

Introduction

Chondrosarcomas are the third most common bone tumors, after myelomas and osteosarcomas. Chondrosarcomas are rapidly progressive, pathologically diverse, and highly malignant, and to date, surgical resection remains the primary treatment for these sarcomas. They have the potential for distant metastasis [1]. The invasion of tumor cells is a complex, multistage process. MMPs play important roles in these processes because their proteolytic activities assist in the degradation of the ECM and basement membranes [4,5]. It has been reported that MMP-2 plays a critical role in ECM turnover and cell-cell interactions as well as metastases of chondrosarcomas [8]

Methods

Results

Conclusion