Abstract 5092: Metabolomic profiling of Oct-1 and c-myc deficient cells to obtain clinical and biological insights into tumorigenicity

Abstract Oct-1 and C-myc have recently been shown to be pro-tumorigenic and their expression is increased in various cancers. Despite recent surge in understanding the role of pluripotency related transcription factors of stem cells in tumorigenicity, little is understood of the role of pluripotency factors oct-1, c-myc, and oct-1 in cancer metabolism. We have used metabolic profiling of oct-1 and c-myc deficient and overexpressed cells to characterize intermediary metabolism and identify the critical nutrients in cancer metabolism. Cancer cell metabolism was investigated using systems biology tools such as metabolic flux analysis (MFA) to reveal intracellular ES cell metabolic flux distribution. Metabolic flux analysis (MFA) refers to a methodology whereby intracellular fluxes (i.e. conversion rates of metabolites through individual reactions) are calculated using a stoichiometric model for the major intracellular reactions and applying mass balances around intracellular metabolites. MFA is a powerful approach for understanding and comparing different metabolic states, and offer insights into the functional capabilities of a metabolic network. The power of this approach is that it takes into account a large set of measurements as well as the complex inter-dependence among the various pathways due to the sharing of a common pool of co-factors such as NADH, NADPH, thus providing a more complete and integrated picture of the metabolic state than isolated measurements relevant to a few pathways. Given that the turnover rate of intracellular metabolites is very fast compared to the time scale of perturbations imparted on the cells, we can assume a “pseudo-steady-state” whereby intracellular levels of metabolites do not change significantly. Under these conditions, the intracellular fluxes are linearly related to measured rates of uptake and release of extracellular metabolites. Since, the metabolites produced by oct-1 and c-myc deficient cells present a unique signature which is different from the metabolic profile of oct-1 and c-myc over expressed cells, we hypothesized that metabolic profiling based approach could lead to understanding of the role of these factors in cancer metabolism. The developed strategy first revealed pathways that were down regulated in the c-myc and oct-1 deficient cells. Second, the obtained optimal flux solutions were used to guide the up-regulation of various pathways and hence, determining the appropriate nutrient and hormonal supplements necessary for loss of oncogenic transformations. Combined biological and clinical studies using metabolic profiling of oct-1 and c-myc deficient and overexpressed cells is likely to have a major impact on the development of therapeutics targeting metabolism in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5092.