Abstract
Cancer cells re-program their metabolic machinery in order to satisfy their bioenergetic and biosynthetic requirements. A critical aspect of the re-programming of cancer cell metabolism involves changes in the glycolytic pathway (referred to as the "Warburg effect"). As an outcome of these changes, much of the pyruvate generated via the glycolytic pathway is converted to lactic acid, rather than being used to produce acetyl-CoA and ultimately, the citrate which enters the citric acid cycle. In order to compensate for these changes and to help maintain a functioning citric acid cycle, cancer cells often rely on elevated glutamine metabolism. Recently, we have found that this is achieved through a marked elevation of glutaminase activity in cancer cells. Here we further consider these findings and the possible mechanisms by which this important metabolic activity is regulated.
Highlights
Our initial efforts to identify novel small molecule inhibitors that block malignant transformation were directed at Rho family GTPase-signaling pathways
We have recently discovered a new role for Rho GTPases in cancer progression through a previously unappreciated connection to cellular metabolism [21]
We have found that the hyper-activation of Cdc42 as well as related Rho GTPases (e.g. Rac1, RhoA and RhoC) signals the activation of a mitochondrial enzyme, glutaminase, that plays a key role in glutamine metabolism by hydrolyzing glutamine to glutamate and ammonia
Summary
Our initial efforts to identify novel small molecule inhibitors that block malignant transformation were directed at Rho family GTPase-signaling pathways. Signals originating from members of this GTPase family have been shown to be important for a broad array of cellular processes ranging from actin cytoskeletal rearrangements to cell polarity, migration, and cell-cycle progression [1] These GTPases have been implicated in a variety of diseases and developmental disorders, with a number of lines of evidence linking Rho family members to cancer [2]. A second major set of changes in cancer metabolism that helps to accommodate the alterations in the glycolytic pathway, results in a shift to increased rates of glutamine metabolism This occurs through the accelerated hydrolysis of glutamine to glutamate, as catalyzed by mitochondrial glutaminase activity, and the subsequent conversion of glutamate to α-ketoglutarate, catalyzed by glutamate dehydrogenase. The enhanced production of α-ketoglutarate that is the outcome of elevated glutamine metabolism helps to maintain the citric acid cycle in cancer cells, given the loss of the input from pyruvate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
