TY - JOUR
T1 - Integrin regulation of β-catenin signaling in ovarian carcinoma
AU - Burkhalter, Rebecca J.
AU - Symowicz, Jaime
AU - Hudson, Laurie G.
AU - Gottardi, Cara J.
AU - Stack, M. Sharon
PY - 2011/7/1
Y1 - 2011/7/1
N2 - Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and β-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3β, elevated levels of nuclear β-catenin, increased β-catenin-regulated promoter activation, and transcriptional activation of Wnt/β-catenin target genes. Blocking β-catenin transcriptional control with inhibitor of β-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for β-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased β-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/β-catenin signaling in the absence of activating mutations in this pathway.
AB - Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and β-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3β, elevated levels of nuclear β-catenin, increased β-catenin-regulated promoter activation, and transcriptional activation of Wnt/β-catenin target genes. Blocking β-catenin transcriptional control with inhibitor of β-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for β-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased β-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/β-catenin signaling in the absence of activating mutations in this pathway.
UR - http://www.scopus.com/inward/record.url?scp=79958792449&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958792449&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.199539
DO - 10.1074/jbc.M110.199539
M3 - Article
C2 - 21518759
AN - SCOPUS:79958792449
VL - 286
SP - 23467
EP - 23475
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 26
ER -