Colchicine induces membrane-associated activation of matrix metalloproteinase-2 in osteosarcoma cells in an S100A4-independent manner.
Like the metastasis-associated protein S100A4, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in physiological and pathological conditions. Previously, we showed that S100A4 is involved in the regulation of MMPs and TIMPs, and in the present work we have investigated whether the anti-inflammatory and microtubule-disrupting drug colchicine has an effect on the expression of these proteins in osteosarcoma cell lines (OHS) with high and low levels of S100A4. Colchicine treatment of the various OHS cells resulted in an increased expression of MT1-MMP and TIMP-2 mRNA, and a corresponding increase of these two proteins in isolated cell membranes. Colchicine-treated cells produced more of the activated form of MMP-2 than control cells. However, the drug did not affect the amount of MMP-2 and TIMP-1 mRNA or protein, and it reduced the S100A4 mRNA expression. Isolated cell membranes from the colchicine-treated cells were more effective in activating exogenous proMMP-2 than membranes from control cells, and inhibitory studies indicated that it was the colchicine-induced increase in MT1-MMP that caused the increased activation of endogenous MMP-2. A peptide inhibitor of nuclear factor kappaB nuclear translocation, SN50, blocked the colchicine-induced activation of proMMP-2 and reduced the synthesis of MMP-2 in colchicine-treated cells, but not in control cells. It can be concluded that colchicine modulates the expression of MT1-MMP and TIMP-2 and hence the activation of proMMP-2 independently of the S100A4 level in osteosarcoma cells.
Loennechen
Thrina
T
Department of Pharmacology, Institute of Pharmacy, University of Tromsø, 9037 Tromsø, Norway.
Mathisen
Berit
B
Hansen
Janne
J
Lindstad
Rune I
RI
El-Gewely
Sara Ann
SA
Andersen
Kristin
K
Maelandsmo
Gunhild M
GM
Winberg
Jan-Olof
JO
D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006074:Gout Suppressants / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D012516:Osteosarcoma / Q000201:enzymology* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D006074:Gout Suppressants; D016328:NF-kappa B; D010455:Peptides; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C118258:SN50 peptide; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C077591:S100A4 protein, human; D020778:Matrix Metalloproteinase 2; D003078:Colchicine