title: AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma.
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.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, No, 91, Hsueh-Shih Road, Taichung, Taiwan. chtang@mail.cmu.edu.tw.
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.forename: Min-Huan
authors.initials: MH
authors.lastname: Wu
authors.forename: Chin-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.forename: Horng-Chaung
authors.initials: HC
authors.lastname: Hsu
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D054405:Chemokine CCL3 / Q000378:metabolism*; D002813:Chondrosarcoma / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C515429:CCL3 protein, human; C584933:CCR5 protein, human; D054405:Chemokine CCL3; D016328:NF-kappa B; D019713:Receptors, CCR5; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
references.citation: J Orthop Res. 2007 Aug;25(8):1106-14
references.pmid: 17415781
references.citation: Bioessays. 1998 Dec;20(12):1039-46
references.pmid: 10048303
references.citation: Cancer Prev Res (Phila). 2012 Nov;5(11):1260-72
references.pmid: 23034147
references.citation: Carcinogenesis. 2009 Feb;30(2):258-68
references.pmid: 19126648
references.citation: Mol Cell Biol Res Commun. 2000 Jul;4(1):15-9
references.pmid: 11152622
references.citation: Clin Sci (Lond). 2013 Apr;124(8):491-507
references.pmid: 23298225
references.citation: Exp Dermatol. 2003 Apr;12(2):109-25
references.pmid: 12702139
references.citation: Biochem Pharmacol. 2011 Jun 1;81(11):1286-95
references.pmid: 21453685
references.citation: Arthritis Rheum. 2012 Oct;64(10):3344-54
references.pmid: 22674286
references.citation: PLoS One. 2013;8(1):e53974
references.pmid: 23320110
references.citation: Biochim Biophys Acta. 2013 Jun;1830(6):3355-64
references.pmid: 23523690
references.citation: J Cell Physiol. 2012 Aug;227(8):3016-26
references.pmid: 21959927
references.citation: J Exp Med. 1993 Jun 1;177(6):1821-6
references.pmid: 7684437
references.citation: Rev Diabet Stud. 2009 Spring;6(1):13-36
references.pmid: 19557293
references.citation: Clin Exp Metastasis. 2006;23(5-6):291-300
references.pmid: 17086356
references.citation: J Cell Physiol. 2009 Oct;221(1):98-108
references.pmid: 19475568
references.citation: Bone. 2010 Apr;46(4):1122-30
references.pmid: 20053385
references.citation: J Orthop Res. 1998 Sep;16(5):585-90
references.pmid: 9820282
references.citation: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references.pmid: 16680569
references.citation: Differentiation. 2002 Dec;70(9-10):498-505
references.pmid: 12492492
references.citation: Front Oncol. 2013 Mar 18;3:53
references.pmid: 23508546
references.citation: Cancer Metastasis Rev. 2008 Dec;27(4):679-90
references.pmid: 18465089
references.citation: Sci China Life Sci. 2011 Oct;54(10):976-9
references.pmid: 22038011
references.citation: Oncogene. 2007 Apr 12;26(17):2491-501
references.pmid: 17099730
references.citation: J Cell Biochem. 2009 May 15;107(2):345-56
references.pmid: 19301259
references.citation: Prostate. 2009 Dec 1;69(16):1781-9
references.pmid: 19676095
references.citation: Diabetes Metab J. 2013 Feb;37(1):1-21
references.pmid: 23441028
references.citation: J Immunol. 2003 Dec 1;171(11):6052-8
references.pmid: 14634118
references.citation: Nat Rev Cancer. 2002 Mar;2(3):161-74
references.pmid: 11990853
references.citation: Am J Pathol. 2012 Jan;180(1):365-74
references.pmid: 22037251
references.citation: J Immunol. 2008 Nov 1;181(9):6384-93
references.pmid: 18941229
references.citation: Arthritis Rheum. 2010 Dec;62(12):3615-24
references.pmid: 20862675
references.citation: Carcinogenesis. 2009 Oct;30(10):1651-9
references.pmid: 19549705
references.citation: Bone. 2009 Feb;44(2):233-42
references.pmid: 19038372
references.citation: Cancer Biol Ther. 2012 Sep;13(11):1123-40
references.pmid: 22825326
references.citation: Oncogene. 2013 Feb 14;32(7):849-60
references.pmid: 22469976
references.citation: Bone. 2013 Jan;52(1):259-67
references.pmid: 23059626
references.citation: Int J Dev Biol. 2004;48(5-6):489-96
references.pmid: 15349823
references.citation: Cancer Res. 2009 May 1;69(9):4001-9
references.pmid: 19383907