Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of beta(2)-microglobulin (beta 2M) in ovarian tumorigenesis

Abstract

In this study, we investigated a possible mechanism of beta(2)-microglobulin (beta M-2) function in cancer metastases in vitro, using a human ovarian carcinoma cell line. beta M-2, a modulator acts as a cell growth-promoting and cellular signaling factors, was identified as a dickkopf-3 (DKK-3) interacting protein. We also observed that DKK-3 suppresses endothelial cell angiogenesis of beta M-2 through vascular endothelial growth factor receptor-2 (VEGFR-2) in tumorigenesis. Luciferase activity was remarkably reduced by the transfection of DKK-3 in a dose-dependent manner. In addition, over-expression of beta M-2 activates cell growth by suppressing DKK-3-induced apoptosis. The effect of beta M-2 on cell cycle and apoptosis-regulatory components was also confirmed through the silencing of beta M-2 expression. Furthermore, induction of beta M-2-mediated VEGFR-2/Akt/mTOR phosphorylation and tumor angiogenesis was significantly suppressed by over-expression of DKK-3. Taken together, our results suggest an underlying mechanism for an increase of beta M-2-related activity in ovarian tumor cells. (C) 2015 Elsevier Inc. All rights reserved.