Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis

Boh-Ram Kim; Eun-Ju Lee; Seung Hee Seo; Seung-Hoon Lee; Seung Bae Rho

doi:10.1016/j.cellsig.2015.08.008

Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis

Cell Signal. 2015 Nov;27(11):2150-9. doi: 10.1016/j.cellsig.2015.08.008. Epub 2015 Aug 14.

Authors

Boh-Ram Kim¹, Eun-Ju Lee², Seung Hee Seo¹, Seung-Hoon Lee³, Seung Bae Rho⁴

Affiliations

¹ Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
² Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Chung-Ang University Hospital, 224-1, Heuksuk-Dong, Dongjak-Gu, Seoul 156-755, Republic of Korea.
³ Department of Life Science, Yong In University, 470, Samga-dong, Cheoin-gu, Yongin-si, Gyeonggi-do 449-714, Republic of Korea.
⁴ Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: sbrho@ncc.re.kr.

PMID: 26278164
DOI: 10.1016/j.cellsig.2015.08.008

Abstract

In this study, we investigated a possible mechanism of β2-microglobulin (β2M) function in cancer metastases in vitro, using a human ovarian carcinoma cell line. β2M, 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 β2M 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 β2M activates cell growth by suppressing DKK-3-induced apoptosis. The effect of β2M on cell cycle and apoptosis-regulatory components was also confirmed through the silencing of β2M expression. Furthermore, induction of β2M-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 β2M-related activity in ovarian tumor cells.

Keywords: Anti-apoptotic effect; DKK-3; Ovarian tumor metastasis; Protein–protein interaction; β2M.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Apoptosis / genetics
Apoptosis / physiology
Cell Cycle Checkpoints / genetics
Cell Line, Tumor
Cell Proliferation / genetics
Cell Transformation, Neoplastic / pathology
Chemokines
Female
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Intercellular Signaling Peptides and Proteins / metabolism*
Luciferases / metabolism
Neoplasm Metastasis / pathology
Neovascularization, Pathologic / pathology
Ovarian Neoplasms / pathology*
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism*
RNA Interference
RNA, Small Interfering
Signal Transduction / genetics
TOR Serine-Threonine Kinases / metabolism*
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
beta 2-Microglobulin / genetics
beta 2-Microglobulin / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Chemokines
DKK3 protein, human
Intercellular Signaling Peptides and Proteins
RNA, Small Interfering
beta 2-Microglobulin
Luciferases
MTOR protein, human
KDR protein, human
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases