Integrin αvβ3/vitronectin interaction affects expression of the urokinase system in human ovarian cancer cells

被引:56
作者
Hapke, S
Kessler, H
de Prada, NA
Benge, A
Schmitt, M
Lengyel, E
Reuning, U
机构
[1] Tech Univ Munich, Klin Forschergrp, Frauenklin, Klinikum Rechts Isar, D-81675 Munich, Germany
[2] Tech Univ Munich, Inst Organ Chem & Biochem, D-85747 Garching, Germany
[3] Univ Calif San Francisco, Ctr Canc, Dept Obstet Gynecol & Reprod Sci, Canc Res Inst, San Francisco, CA 94143 USA
关键词
D O I
10.1074/jbc.M100181200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The urokinase type plasminogen activator (uPA), together with its receptor uPAR and the plasminogen activator inhibitor type-1 (PAI-1) plays a pivotal role during tumor invasion and metastasis. Integrins, via interaction with the extracellular matrix (ECM), control cell adhesion and motility, The two systems are functionally linked because uPAR and PAI-1 bind to the ECM component vitronectin (VN), Because integrin signaling alters gene expression patterns, we investigated whether the expression levels of uPA, uPAR, and PAI-1 are affected by ECM/integrin interactions. Expression of uPA, uPAR, and PAI-1 was significantly enhanced when human ovarian cancer cells (OV-MZ-6) were cultivated on fibronectin or collagen type , In contrast, VN induced down-regulation of uPA and uPAR while increasing PAI-1 by up to 4-fold. VN-dependent decrease of uPA protein was paralleled by a significant reduction of uPA promoter activity that was even more pronounced upon alpha (v)beta (3) overexpression and depended on the presence of intact Rel protein-binding sites. The activity of Rel transcription factors was also significantly reduced upon alpha (v)beta (3)-mediated cell adhesion to VN, The activity of the Rel-unresponsive PAI-1 promoter was up to 5-fold induced as a function of alpha (v)beta (3)/VN interaction. Thus, the balance between available concentrations of uPA, uPAR, PAI-1, and integrins in human ovarian cancer cells might provide a switch within the regulation of their invasive phenotype.
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页码:26340 / 26348
页数:9
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