Abstract
A lot of parallels have been described between invasion of malignant tumor cells and leukocyte movement during inflammatory responses. Concerning these similarities, we investigated the function of cytokine-suppressive anti-inflammatory drugs (CSAIDs), which act via inhibition of stress-activated MAP-kinases, in regulation of expression of proteolytic enzymes and in vitro invasion of malignant melanoma cells. The p38MAPK inhibitor SB203580 reduced matrigel invasion of MeWo cells by 60%, while the MEK-1 inhibitor PD98059 did not have any effect on invasion. Active p38MAPK was detected in MeWo cells by immunoblotting and confocal microscopy. Cells showed a constitutive expression of matrix-metalloproteinase (MMP)-2 as well as tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 mRNAs. Expression of MMP-1 or urokinase-type plasminogen activator (uPA) was not detected by Northern blot. Inhibition of p38MAPK by the specific inhibitor SB203580 resulted in downregulation of MMP-2 mRNA and protein levels as well as gelatinolytic activity, while expression levels of TIMP-1 and TIMP-2 mRNAs were not changed. The specific MEK-1 inhibitor PD98059 did not change expression of MMP-2 or TIMPs. Neither SB203580 nor PD98059 changed proliferation of cells. The results suggest that stress-activated protein kinases like p38MAPK are involved in regulation of expression of MMP-2 as well as in vitro invasion of malignant melanoma cells. Inhibitors of p38MAPK may be promising substances to interfere with a signaling cascade associated with invasion of malignant tumor cells.
MeSH terms
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Blotting, Northern
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Cell Division / drug effects
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology*
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Flavonoids / pharmacology*
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Gelatin / metabolism
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Gene Expression Regulation, Neoplastic / drug effects*
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Imidazoles / pharmacology*
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MAP Kinase Kinase 1
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MAP Kinase Signaling System / drug effects*
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Matrix Metalloproteinase 2 / biosynthesis*
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Matrix Metalloproteinase 2 / genetics
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Melanoma / enzymology*
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Melanoma / genetics
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase Kinases / physiology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / physiology
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Neoplasm Invasiveness*
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / physiology
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / physiology
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Pyridines / pharmacology*
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-2 / biosynthesis
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Neoplasm Proteins
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Pyridines
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RNA, Messenger
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RNA, Neoplasm
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Tissue Inhibitor of Metalloproteinase-1
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Tissue Inhibitor of Metalloproteinase-2
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Gelatin
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases
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Matrix Metalloproteinase 2
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one