Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc genotype
Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc genotype
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DOI：
10.1093/carcin/23.6.1065
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发表时间：
2002-06-01
期刊：
影响因子：
4.7
通讯作者：
Hord, NG
中科院分区：
文献类型：
--
作者：
Fenton, JI;Wolff, MS;Hord, NG
结肠上皮细胞迁移是正常分化细胞功能所必需的。这种迁移表型依赖于野生型腺瘤性结肠息肉病（APC）的表达。使用具有不同Apc基因型的非致瘤性鼠结肠上皮细胞系，即年轻成年小鼠结肠（YAMC; Apc（+/+））和永生小鼠/Min结肠上皮（IMCE; Apc（Min/+）细胞）来评估Apc基因型、细胞运动性和基质金属蛋白酶（MMP）活性之间的关联。用表皮生长因子（EGF; 1、10和25 ng/ml）、肝细胞生长因子（HGF; 1、10和25 ng/ml）和/或姜黄素（0.1-100 μ M）处理细胞。EGF（25 ng/ml）和HGF（25 ng/ml）作用24 h后，YAMC细胞的迁移反应明显强于IMCE细胞（P < 0.05）。姜黄素治疗诱导更大或等效的迁移反应IMCE比YAMC细胞。当迁移细胞用Ilomastat（（R））（MMP抑制剂）处理时，两种细胞类型的迁移都受到抑制。高浓度的伊洛马司他（（R））（25和50 μ M）抑制两种细胞类型的迁移，而低浓度（10 μ M）抑制HGF诱导的IMCE迁移。在最高浓度的伊洛马司他（（R））（50 μ M）下，姜黄素诱导的迁移在两种细胞类型中都受到抑制。膜型-1（MT 1）-MMP的免疫定位分析表明，迁移与这种蛋白质从内质网到质膜的再分布有关。添加针对MT 1-MMP或MT 1、2-和3-MMP的混合物的中和多克隆抗体分别证明了在两种细胞类型中的细胞迁移的部分或完全抑制。这些数据提供了第一个证据表明，在非致瘤性小鼠结肠上皮细胞的迁移是：（i）诱导的EGF和HGF的Apc基因型依赖的方式，（ii）依赖于MT-MMP活性和（iii）诱导的姜黄素的Apc基因型无关的方式。这些数据表明姜黄素可能诱导Apc杂合细胞克服缺陷细胞迁移的潜在机制，这是一种与细胞分化和凋亡相关的表型。
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; Apc(Min/+) 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 muM). 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((R)) (MMP inhibitor), migration was inhibited in both cell types. High concentrations of Ilomastat((R)) (25 and 50 muM) inhibited migration in both cell types, while low concentrations (10 muM) inhibited HGF-induced IMCE migration. Curcumin-induced migration was inhibited in both cell types at the highest concentration of Ilomastat((R)) (50 muM). 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.