Abstract SY42-03: One carbon metabolism and cancer

Abstract

Abstract Cancer cells adapt their metabolism to allow for growth and proliferation, while maintaining survival under conditions of fluctuating nutrient availability. Recent studies have shown that cancer cells are highly dependent on the non-essential amino acid serine. We have found a key requirement for serine is to maintain the one carbon cycle needed for nucleotide synthesis. Serine depletion impedes nucleotide synthesis and inhibits proliferation, a response that can be rescued by providing glycine and one-carbon units in the form of formate. More recently, we have been examining the fate of serine and the effect of serine depletion on other pathways that require one-carbon metabolism, such as NADPH production and the methionine cycle. We found that the adaptation to serine starvation involves diversion of glycolytic intermediates into the de novo SSP, resulting in a greater dependence on OXPHOS to provide energy. Interestingly, the serine produced during this period of adaptation is channeled into antioxidant defense through generation of both glutathione and NADPH, to help buffer the ROS produced from this increase in OXPHOS. Defects in the ability to make this adaptation and limit ROS, as seen in cells lacking p53, impedes the ability of cells to cope with a loss of exogenous serine. Serine is also required to support the S-adenosyl methionine (SAM) cycle, although surprisingly we have found that this reflected a requirement for ATP rather than one-carbon units. As a consequence, serine depletion caused a decrease in the conversion of methionine to SAM and a rapid remodeling of DNA methylation. We are currently examining the consequences on gene specific methylation and expression. Funded by CR-UK and ERC Citation Format: Oliver Maddocks, Christiaan Labuschagne, Karen H. Vousden. One carbon metabolism and cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY42-03. doi:10.1158/1538-7445.AM2015-SY42-03