A role for activated Cdc42 in glioblastoma multiforme invasion

Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitu...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2016-08, Vol.7 (35), p.56958-56975
Main Authors: Okura, Hidehiro, Golbourn, Brian J, Shahzad, Uswa, Agnihotri, Sameer, Sabha, Nesrin, Krieger, Jonathan R, Figueiredo, Carlyn A, Chalil, Alan, Landon-Brace, Natalie, Riemenschneider, Alexandra, Arai, Hajime, Smith, Christian A, Xu, Songli, Kaluz, Stefan, Marcus, Adam I, Van Meir, Erwin G, Rutka, James T
Format: Article
Language:English
Subjects:
Animals
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
cdc42 GTP-Binding Protein - metabolism
Cell Adhesion
Cell Line, Tumor
Cell Movement
Cell Survival
Disease Progression
Disease-Free Survival
Doxycycline - chemistry
Focal Adhesion Kinase 1 - metabolism
Gene Expression Regulation, Neoplastic
Genes, Dominant
Glioblastoma - metabolism
Glioblastoma - pathology
Glioma - metabolism
Glioma - pathology
Humans
Mice
Neoplasm Invasiveness
Neoplasm Transplantation
Phenotype
Phosphorylation
Pseudopodia - metabolism
ras GTPase-Activating Proteins - metabolism
Research Paper
RNA, Small Interfering - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.10925