RhoGDI deficiency induces constitutive activation of Rho GTPases and COX-2 pathways in association with breast cancer progression

Rho GDP Dissociation Inhibitor (RhoGDI) is a key regulator of Rho GTPases. Here we report that loss of RhoGDI significantly accelerated xenograft tumor growth of MDA-MB-231 cells in animal models. At the molecular level, RhoGDI depletion resulted in constitutive activation of Rho GTPases, including...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2015-10, Vol.6 (32), p.32723-32736
Main Authors: Bozza, William P, Zhang, Yaqin, Hallett, Kory, Rivera Rosado, Leslie A, Zhang, Baolin
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - enzymology
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cyclooxygenase 2 - genetics
Cyclooxygenase 2 - metabolism
Disease Progression
Enzyme Activation
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Mice, Nude
Neoplasm Staging
Protein Transport
Research Paper
rho GTP-Binding Proteins - genetics
rho GTP-Binding Proteins - metabolism
rho Guanine Nucleotide Dissociation Inhibitor alpha - deficiency
rho Guanine Nucleotide Dissociation Inhibitor alpha - genetics
RNA Interference
Signal Transduction
Time Factors
Transfection
Tumor Burden
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:Rho GDP Dissociation Inhibitor (RhoGDI) is a key regulator of Rho GTPases. Here we report that loss of RhoGDI significantly accelerated xenograft tumor growth of MDA-MB-231 cells in animal models. At the molecular level, RhoGDI depletion resulted in constitutive activation of Rho GTPases, including RhoA, Cdc42, and Rac1. This was accompanied by Rho GTPase translocation from the cytosol to membrane compartments. Notably, COX-2 protein levels, mRNA expression, and biological activity were markedly increased in RhoGDI-deficient cells. The upregulated expression of COX-2 was directly associated with increased Rho GTPase activity. Further, we assessed the expression level of RhoGDI protein in breast tumor specimens (n = 165) by immunohistochemistry. We found that RhoGDI expression is higher in the early stages of breast cancer followed by a significant decrease in malignant tumors and metastatic lesions (p < 0.01). These data suggest that downregulation of RhoGDI could be a critical mechanism of breast tumor development, which may involve the hyperactivation of Rho GTPases and upregulation of COX-2 activity. Additional studies are warranted to evaluate the therapeutic potential of inhibiting Rho GTPases and COX-2 for treating breast cancers.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.5416