Cancer cells undergo metabolic reprogramming that results in altered utilization of glucose and glutamine as fuels to provide tumors with an advantage for continued growth and proliferation. The mitochondrial sirtuin, SIRT3, is a deacetylase known to promote mitochondrial oxidative metabolism and decrease oxidative stress. In addition, work from my laboratory showed that one of the functions of SIRT3 as a tumor suppressor is to repress glucose metabolism, specifically the Warburg effect, by decreasing ROS to destabilize the transcription factor HIF1alpha, known to increase expression of target glycolytic genes. Moreover, decreased levels of SIRT3 were observed in various types of cancer. Although SIRT3 has been shown to activate other metabolic pathways, such as fatty acid oxidation, the role of SIRT3 in the regulation of glutamine metabolism in cancer has not been examined. My preliminary data shows that loss of SIRT3 increases glutamine uptake and ammonia production, phenotypes reversed by overexpression of SIRT3 in breast cancer cells. In addition, loss of SIRT3 results in decreased TCA cycle metabolite levels and increased glutathione levels. These data point to a connection between SIRT3 and glutamine metabolism, an exciting and novel area by which sirtuins may regulate tumor cell metabolism - an area that remains to be studied. This research proposal aims to: 1) determine the contribution of glutamine to glutathione synthesis and other anabolic precursors, 2) determine the role of glutathione in cancer cells lacking SIRT3, and 3) elucidate the mechanism(s) by which SIRT3 regulates glutamine metabolism.
In addition to increased glucose metabolism, tumor cells have increased glutamine metabolism providing them with an advantage for growth, proliferation, and survival. My laboratory has discovered that SIRT3, a protein deacetylase known to regulate metabolism, functions as a tumor suppressor by destabilizing HIF1-alpha thereby repressing the Warburg effect in tumor cells. My preliminary data links SIRT3 to the regulation of glutamine metabolism, and my ultimate goal is to mechanistically determine how SIRT3 regulates glutamine utilization in tumor cells to identify potential avenues or targets for development of novel therapies for treatment of cancer.
