title: Upregulation of tissue inhibitor of matrix metalloproteinases-1 confers the anti-invasive action of cisplatin on human cancer cells.
abstract: Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the anti-invasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time- and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.
authors: Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors: R
authors: R
authors: Ramer
authors: K
authors: K
authors: Eichele
authors: B
authors: B
authors: Hinz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; C059485:matrigel; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D002945:Cisplatin