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

Abstract

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.

The cytotoxic type 3 secretion system 1 of Vibrio rewires host gene expression to subvert cell death and activate cell survival pathways

“…3B, Fig. 4) (51). Perhaps the increase of PTGS2 expression and predicted activation of Rho GTPase signaling in POR3:T3SS1 + –infected fibroblasts are due to a specific suppression of RhoGDI signaling by T3SS1 effectors.…”

Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

“…What is more, regarded as a therapeutic target of pancreatic cancer, ARHGDIA (also known as RhoGDI) has been actually proved to be associated with the proliferation and invasion process of the pancreatic tumorigenesis which may further affect the prognosis of various patients [ 51 ]. The expression quantity of such gene, ARHGDIA, as the specific negative regulator of Rho protein exchange reactions, has been widely confirmed to be downregulated in tumors, which further induce the activation of survival associated Rho GTPases and promote the progression of various tumors [ 55 – 57 ]. As for specific mutations that may affect the biological function of such gene, coincidentally, specific triple Y156F/S101A/S174A-RhoGDI mutation has been confirmed to be related to the progression of pancreatic cancer [ 58 ].…”

Development of Substrate‐Derived Sirtuin Inhibitors with Potential Anticancer Activity

“…Somea re tumor suppressive and others contributetotumor formation. [29] Notably,i nt his study RhoGDIa expression was knocked-down using siRNA, which might be different from switching-off many but maybe not all functionalities of RhoG-DIa by post-translational modifications without affecting the overall protein level. [26] Elevated levelso fR hoGDIa were found in nonsmall cell lung carcinomac ells and RhoGDIb mRNA levels were increased in ovarian adenocarcinomac orrelating with the malignancyo ft he tumors.…”

“…RhoGDIa expression was elevated at early phases of breast cancerd evelopment while it was decreased at later stages. [29] Notably,i nt his study RhoGDIa expression was knocked-down using siRNA, which might be different from switching-off many but maybe not all functionalities of RhoG-DIa by post-translational modifications without affecting the overall protein level.…”