Flavonoids promote cell migration in nontumorigenic colon epithelial cells differing in Apc genotype: implications of matrix metalloproteinase activity.
Colonic epithelial cell migration is required for movement up to the apex of the crypt and, hence, normal differentiated cell function. This migratory phenotype is dependent upon wild-type adenomatous polyposis coli (Apc) expression. The purpose of this study is to determine whether specific flavonoids induce cell migration in colon epithelial cells either wild type or heterozygous for Apc genotype. Nontumorigenic murine colon epithelial cell lines with distinct Apc genotypes, young adult mouse colon (YAMC; Apc+/+) cells, and Immortomouse/Min colon epithelial (IMCE; Apc(Min/+)) cells were used to assess the ability of specific flavonoids to induce cell migration relative to migration induced by hepatocyte growth factor (HGF). The citrus flavanones naringenin and hesperetin did not induce cell migration comparable with HGF in either cell type. However, the glycosylated forms of these flavanones, naringin and hesperidin, induced migration differentially in YAMC and IMCE cells. Specifically, naringin and hesperidin induced the greatest migratory response in IMCE cells at 1 microM (P < 0.01) and induced migration greater than untreated control cells (P < 0.05) but equal to HGF-treated cells. In YAMC cells, hesperidin did not induce migration except at the 100-microM concentration. Apigenin induced migration in IMCE cells at 1 (P < 0.05) and 50 microM (P < 0.01) and did not induce migration in the YAMC cells. Catechin induced migration at the highest concentration (300 microM) only in the IMCE cells, whereas epicatechin induced migration at the lowest concentration only (1 microM) in IMCE cells. Overall, the glycosylated citrus flavanones induced the greatest migratory response at the lowest concentration in IMCE cells. Co-treatment of IMCE cells with the global matrix metalloproteinase (MMP) inhibitor Ilomastat in the presence of naringin, hesperidin, or apigenin demonstrated that flavonoid-induced migration was dependent on MMP activity. Induction of the migratory phenotype by flavonoids in these models of preneoplastic epithelial cells suggests a novel mechanism for colon cancer prevention.
Fenton
Jenifer I
JI
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
Hord
Norman G
NG
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D017491:Genes, APC; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice
D005419:Flavonoids; D017228:Hepatocyte Growth Factor; D020782:Matrix Metalloproteinases