Rho GTPases in cancer

Abstract

Rho GTPases play well-established roles in regulating cell growth and migration. Here we review how alterations in the functioning of their upstream activators [guanine nucleotide exchange factors (GEFs)] and negative regulators (GTPase-activating proteins) can contribute to the development of the transformed state. We also describe a more recent discovery of a novel signaling connection between these GTPases and elevated glutamine metabolism in cancer cells. This was based on the identification of a small molecule inhibitor that blocks the transformation of fibroblasts by oncogenic Dbl (for Diffuse B cell lymphoma), a Rho GEF, as well as inhibits the growth of human breast cancer and B lymphoma cells, and shrinks tumors induced by these cancer cells in mice. The effects of the small molecule inhibitor were specific for transformed/cancer cells, as it did not inhibit the growth of normal cells. The target of this inhibitor was shown to be an isoform of the metabolic enzyme glutaminase (GLS1), which catalyzes the hydrolysis of glutamine to glutamate. Transformed/cancer cells show markedly elevated levels of GLS1 activity, which are dependent on the activation of Rho GTPases. We further discuss that an important outcome of the metabolic changes exhibited by cancer cells is the generation of vesicular structures (microvesicles) that contain signaling proteins, metabolic enzymes, RNA transcripts, and microRNA. Microvesicles, by transferring these components to recipient cells, are capable of conferring transformed properties on to their acceptor cells and thus have been suggested to play important roles in cancer progression. Collectively, these results shed new light on how Rho GTPases contribute to the development of human malignancies.