Abstract
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.
Highlights
GBM is characterized by uncontrolled tumor cell proliferation, diffuse infiltration into surrounding normal brain tissue, and impairment of neurological function
Expression of CACdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to wild type (WT) and dominant negative (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)
We found that Cdc42 co-localized with filopodia in glioma cells, and Cdc42 knockdown with small interfering RNA (siRNA) decreased filopodia formation and induced a change in shape towards polygonal (A172 and U87MG), or more rounded (U118MG) morphologies, accompanied by a reduction in actin stress fibers (Figure 1B)
Summary
GBM is characterized by uncontrolled tumor cell proliferation, diffuse infiltration into surrounding normal brain tissue, and impairment of neurological function. There is increasing evidence that the small cytoskeletal Rho-GTPases play a primary role in migration and invasion of GBM cells [2,3,4,5]. They regulate complex www.impactjournals.com/oncotarget molecular events by cycling between an inactive GDPbound and active GTP-bound forms [6]. Binding to GTP is prompted by Rho guanine nucleotide exchange factors (GEFs), and GTP hydrolysis is catalyzed by Rho-GTPase activating proteins (GAPs) [7] In their active GTP-bound form, Rho-GTPases are able to interact with numerous effector molecules to initiate downstream responses until GTP hydrolysis returns them into their inactive state [1, 6]
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