Blocking of the interaction between Wnt proteins and their co-receptors contributes to the anti-tumor effects of adenovirus-mediated DKK3 in glioblastoma

Keijiro Hara; Teruyoshi Kageji; Yoshifumi Mizobuchi; Keiko T Kitazato; Toshiyuki Okazaki; Toshitaka Fujihara; Kohei Nakajima; Hideo Mure; Kazuyuki Kuwayama; Tomoyo Hara; Shinji Nagahiro

doi:10.1016/j.canlet.2014.09.045

Blocking of the interaction between Wnt proteins and their co-receptors contributes to the anti-tumor effects of adenovirus-mediated DKK3 in glioblastoma

Cancer Lett. 2015 Jan 28;356(2 Pt B):496-505. doi: 10.1016/j.canlet.2014.09.045. Epub 2014 Oct 6.

Affiliations

¹ Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. Electronic address: [email protected].
² Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
³ Faculty of Medicine, The University of Tokushima Graduate School, Tokushima, Japan.

PMID: 25301448
DOI: 10.1016/j.canlet.2014.09.045

Abstract

The effect of the third member of the Dickkopf family (DKK3) in the Wnt pathway in glioblastoma remains unclear. We first demonstrated the non-specific interaction of Wnt3a and Wnt5a with the receptors LRP6 and ROR2 and the up-regulation of the Wnt pathway in glioblastoma cells. We used an adenovirus vector and found that an increase in DKK3 protein attenuated the expression of Wnt3a, Wnt5a and LRP6, but not of ROR2, and their interaction, thereby affecting both canonical- and non-canonical Wnt downstream cascades. This produced anti-tumor effects in GBM xenograft models. The suppression of Wnt pathways upstream by DKK3 may have promise for the treatment of glioblastoma.

Keywords: DKK3; Glioblastoma; LRP6; Wnt3a; Wnt5a.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing
Adenoviridae / genetics*
Animals
Apoptosis
Blotting, Western
Cell Proliferation
Chemokines
Flow Cytometry
Genetic Vectors / administration & dosage
Glioblastoma / metabolism
Glioblastoma / pathology
Glioblastoma / prevention & control*
Humans
Immunoenzyme Techniques
Immunoprecipitation
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Low Density Lipoprotein Receptor-Related Protein-6 / antagonists & inhibitors*
Low Density Lipoprotein Receptor-Related Protein-6 / genetics
Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptor Tyrosine Kinase-like Orphan Receptors / antagonists & inhibitors*
Receptor Tyrosine Kinase-like Orphan Receptors / genetics
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Wnt Proteins / antagonists & inhibitors*
Wnt Proteins / genetics
Wnt Proteins / metabolism
Wnt-5a Protein
Wnt3A Protein / antagonists & inhibitors*
Wnt3A Protein / genetics
Wnt3A Protein / metabolism
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
Chemokines
DKK3 protein, human
Intercellular Signaling Peptides and Proteins
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
Proto-Oncogene Proteins
RNA, Messenger
WNT3A protein, human
WNT5A protein, human
Wnt Proteins
Wnt-5a Protein
Wnt3A Protein
ROR2 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors