Document Detail

Calcium regulation of matrix metalloproteinase-mediated migration in oral squamous cell carcinoma cells.
MedLine Citation:
PMID:  12194986     Owner:  NLM     Status:  MEDLINE    
Activation of matrix metalloproteinase 2 (MMP-2) has been shown to play a significant role in the behavior of cancer cells, affecting both migration and invasion. The activation process requires multimolecular complex formation involving pro-MMP-2, membrane type 1-MMP (MT1-MMP), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Because calcium is an important regulator of keratinocyte function, we evaluated the effect of calcium on MMP regulation in an oral squamous cell carcinoma line (SCC25). Increasing extracellular calcium (0.09-1.2 mm) resulted in a dose-dependent increase in MT1-MMP-dependent pro-MMP-2 activation. Despite the requirement for MT1-MMP in the activation process, no changes in MT1-MMP expression, cell surface localization, or endocytosis were apparent. However, increased generation of the catalytically inactive 43-kDa MT1-MMP autolysis product and decline in the TIMP-2 levels in conditioned media were observed. The decrease in TIMP-2 levels in the conditioned media was prevented by a broad spectrum MMP inhibitor, suggesting that calcium promotes recruitment of TIMP-2 to MT1-MMP on the cell surface. Despite the decline in soluble TIMP-2, no accumulation of TIMP-2 in cell lysates was seen. Blocking TIMP-2 degradation with bafilomycin A1 significantly increased cell-associated TIMP-2 levels in the presence of high calcium. These data suggest that the decline in TIMP-2 is because of increased calcium-mediated MT1-MMP-dependent degradation of TIMP-2. In functional studies, increasing calcium enhanced MMP-dependent cellular migration on laminin-5-rich matrix using an in vitro colony dispersion assay. Taken together, these results suggest that changes in extracellular calcium can regulate post-translational MMP dynamics and thus affect the cellular behavior of oral squamous cell carcinoma.
Hidayatullah G Munshi; Yi I Wu; Edgardo V Ariztia; M Sharon Stack
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2002-08-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-10-28     Completed Date:  2003-01-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  41480-8     Citation Subset:  IM    
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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MeSH Terms
Calcium / physiology*
Carcinoma, Squamous Cell / enzymology,  pathology*
Cell Movement
Enzyme Activation
Enzyme Precursors / metabolism
Matrix Metalloproteinase 2 / physiology*
Matrix Metalloproteinases, Membrane-Associated
Metalloendopeptidases / physiology
Mouth Neoplasms / enzymology,  pathology*
Tetradecanoylphorbol Acetate / pharmacology
Tissue Inhibitor of Metalloproteinase-2 / analysis
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Enzyme Precursors; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 16561-29-8/Tetradecanoylphorbol Acetate; 7440-70-2/Calcium; EC 3.4.24.-/Matrix Metalloproteinases, Membrane-Associated; EC 3.4.24.-/Metalloendopeptidases; EC Metalloproteinase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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