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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.
Highlights
The Rho family of small GTPases (e.g., Rac1, Cdc42, and RhoA) are molecular switches that transduce extracellular signals to downstream effectors
Accumulating evidence shows that Rho GDP Dissociation Inhibitor (RhoGDI) and D4-GDI are aberrantly expressed in certain types of human cancers [19, 20]
For example while ovarian cancers have been shown to display high levels of both RhoGDI [21, 22] and D4-GDI [23] compared to normal tissue; RhoGDI has been shown to be under expressed in both primary non-small cell lung cancer (NSCLC) and malignant gliomas [24, 25]
Summary
The Rho family of small GTPases (e.g., Rac, Cdc, and RhoA) are molecular switches that transduce extracellular signals to downstream effectors. These proteins control multiple signaling pathways that are essential for normal cellular functions. RhoGDIs add an additional layer of regulation by controlling Rho GTPase subcellular localization and their physical interactions with GEF or GAP proteins, thereby dictating spatial and temporal activation patterns of Rho GTPases [3]. To date there are three human RhoGDIs that have been identified, including RhoGDI (RhoGDI1or RhoGDI-α), D4-GDI (RhoGDI-2 or RhoGDI-β), and RhoGDI-3 Together they are responsible for the regulation of the entire Rho GTPase family consisting of at least 22 members.
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