Notch3 overexpression promotes anoikis resistance in epithelial ovarian cancer via upregulation of COL4A2
CW Brown, AS Brodsky, RN Freiman - Molecular cancer research, 2015 - AACR
CW Brown, AS Brodsky, RN Freiman
Molecular cancer research, 2015•AACROvarian cancer is a lethal disease with the majority of diagnosed women having distant
metastases. Interestingly, although Notch3 overexpression has been correlated with poor
survival in epithelial ovarian cancer (EOC), little is known about its mechanism of action.
Data show that Notch3 specifically promotes anoikis resistance. In addition, data indicate a
positive role for focal adhesion kinase (FAK) as well as downstream signaling kinases such
as Akt and Erk 1/2 in promoting anchorage-independent growth. Mechanistically, both …
metastases. Interestingly, although Notch3 overexpression has been correlated with poor
survival in epithelial ovarian cancer (EOC), little is known about its mechanism of action.
Data show that Notch3 specifically promotes anoikis resistance. In addition, data indicate a
positive role for focal adhesion kinase (FAK) as well as downstream signaling kinases such
as Akt and Erk 1/2 in promoting anchorage-independent growth. Mechanistically, both …
Abstract
Ovarian cancer is a lethal disease with the majority of diagnosed women having distant metastases. Interestingly, although Notch3 overexpression has been correlated with poor survival in epithelial ovarian cancer (EOC), little is known about its mechanism of action. Data show that Notch3 specifically promotes anoikis resistance. In addition, data indicate a positive role for focal adhesion kinase (FAK) as well as downstream signaling kinases such as Akt and Erk 1/2 in promoting anchorage-independent growth. Mechanistically, both mRNA transcript and protein levels of type IV collagen (COL4A2) are reduced when Notch3 levels are decreased and exogenous collagen IV supplementation reverses the anoikis sensitivity. Reduction of COL4A2 expression by RNAI-mediated knockdown induces cell death. Finally, elevated Notch3 expression levels correlate with higher COL4A2 expression in human ovarian tumor specimens.
Implications: These data highlight type IV collagen as a novel therapeutic target for metastatic EOC.
Visual Overview: http://mcr.aacrjournals.org/content/early/2014/11/25/1541-7786.MCR-14-0334/F1.large.jpg
Mol Cancer Res; 13(1); 78–85. ©2014 AACR.
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