Abstract PL08-04: New ways to impact glutamine metabolism in cancer.

Abstract

Abstract Our laboratory has a long-standing interest in understanding the involvement of Rho GTPases in cell growth and migration, which recently led to our discovery of a novel signaling connection between these GTPases and elevated glutamine metabolism in cancer cells. This was based on our identification of a small molecule inhibitor that blocks the transformation of fibroblasts by oncogenic Dbl (for Diffuse B cell lymphoma), a Rho GTPase-activator, 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 are specific for transformed/cancer cells, as it does not inhibit the growth of normal fibroblasts or mammary epithelial cells. We identified the target of this inhibitor 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, due to post-translational modifications (phosphorylation) that are dependent on the activation of Rho GTPases and NFκB, and are blocked by the small molecule inhibitor. Recently, we have shown that an important outcome of the metabolic changes exhibited by cancer cells, that can be prevented by the inhibitor, is the generation of vesicular structures (oncosomes) that contain signaling proteins, metabolic enzymes, RNA transcripts and microRNA. Oncosomes, 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 glutamine metabolism is elevated during tumorigenesis in order to satisfy the ‘glutamine addiction’ of cancer cells, as well as demonstrate the consequences of such metabolic changes and how they might be interrupted. The hope is that these insights will highlight new strategies for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL08-04.