Journal Article

Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in <i>Apc</i> genotype

Jenifer I. Fenton, Margaret S. Wolff, Michael W. Orth and Norman G. Hord

in Carcinogenesis

Volume 23, issue 6, pages 1065-1070
Published in print June 2002 | ISSN: 0143-3334
Published online June 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.6.1065
Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc genotype

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Colonic epithelial cell migration is required for normal differentiated cell function. This migratory phenotype is dependent upon wild-type adenomatous polyposis coli (Apc) expression. Non-tumorigenic murine colon epithelial cell lines with distinct Apc genotypes, i.e. young adult mouse colon (YAMC; Apc+/+) and immortomouse/Min colon epithelial (IMCE; ApcMin/+ cells) were used to assess the association between the Apc genotype, cell motility and matrix metalloproteinase (MMP) activity. Cells were treated with epidermal growth factor (EGF; 1, 10 and 25 ng/ml), hepatocyte growth factor (HGF; 1, 10 and 25 ng/ml) and/or curcumin (0.1–100 μM). EGF (25 ng/ml) and HGF (25 ng/ml) induced a greater migratory response in YAMC compared with IMCE cells after 24 h (P < 0.05). Treatment with curcumin induced a greater or equivalent migratory response in IMCE than YAMC cells. When migrating cells were treated with Ilomastat® (MMP inhibitor), migration was inhibited in both cell types. High concentrations of Ilomastat® (25 and 50 μM) inhibited migration in both cell types, while low concentrations (10 μM) inhibited HGF-induced IMCE migration. Curcumin-induced migration was inhibited in both cell types at the highest concentration of Ilomastat® (50 μM). Immuno-localization analysis of membrane type-1 (MT1)-MMP indicated that migration is associated with the redistribution of this protein from the endoplasmic reticulum to the plasma membrane. Addition of neutralizing polyclonal antibodies against MT1-MMP or a mixture of MT1, 2- and 3-MMPs demonstrated partial or complete inhibition of cell migration in both cell types, respectively. The data provide the first evidence that migration in non-tumorigenic murine colon epithelial cells is: (i) inducible by EGF and HGF in an Apc genotype-dependent manner, (ii) dependent on MT-MMP activity and (iii) inducible by curcumin in an Apc genotype-independent manner. The data suggest a potential mechanism by which curcumin may induce cells heterozygous for Apc to overcome defective cell migration, a phenotype associated with cell differentiation and apoptosis.

Keywords: APC, adenomatous polyposis coli; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IMCE, immortomouse/Min colon epithelial; INF-γ, interferon-γ; MMP, matrix metalloproteinase; MT, membrane type; YAMC, young adult mouse colon.

Journal Article.  4961 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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