AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression i
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RESEARCH
Open Access
AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma Chin-Jung Hsu1,2, Min-Huan Wu3,7, Chin-Yuan Chen3, Chun-Hao Tsai2,4, Horng-Chaung Hsu2,4 and Chih-Hsin Tang3,5,6*
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. Keywords: CCL3, Chondrosarcoma, AMPK, MMP-2, CCR5
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 also have the potential for distant metastasis [1]. Therefore, better strategies of treatment will ultimately require understanding of the molecular mechanisms of the metastasis step of
* Correspondence: [email protected] 3 Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan 5 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan Full list of author information is available at the end of the article
human chondrosarcoma and identifying and specifically targeting. Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites, and grow. Metastasis increases cell motility, induction of vascular and lymphatic angiogenesis, and migration and invasion to other organs [2]. The invasion of tumor cells is a complex, multistage process.
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