Formation of E-cadherin-mediated cell-cell adhesion activates Akt and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells

被引:109
作者
Reddy, P
Liu, LA
Ren, C
Lindgren, P
Boman, K
Shen, Y
Lundin, E
Ottander, U
Rytinki, M
Liu, K [1 ]
机构
[1] Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden
[2] Umea Univ, Dept Clin Sci Obstet & Gynecol, SE-90187 Umea, Sweden
[3] Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden
[4] Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden
关键词
D O I
10.1210/me.2004-0342
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.
引用
收藏
页码:2564 / 2578
页数:15
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