Abstract 1892: Integrated energetics and flux analysis reveals differential metabolic reprogramming in highly and less invasive cancer cells.

Abstract

Abstract Cancer cell metabolism was investigated using systems biology tools such as metabolic flux analysis (MFA) to reveal intracellular cancer cell metabolic flux distribution. To obtain a complete role of nutrient-induced deprivation in metabolic reprogramming of cancer cells, we need to use metabolic flux analysis to determine unknown intracellular fluxes. MFA provides a framework for the estimation of intracellular fluxes and energy balance analysis (EBA) ensures the thermodynamic feasibility of the computed optimal metabolic fluxes. MFA uses stoichiometric and mass balance constraints to compute the intracellular fluxes. Here, we have developed an integrated energy balance and flux balance analysis framework. Our framework allows estimation of intracellular fluxes and reveals specific adaptations and dysregulation of metabolic pathways in ovarian cancer cells as a result of the nutrient (glucose and glutamine) deprivation conditions. Glutamine and glucose are known to be important for cancer cell survival, growth and progression. Thus, there is a strong motivation to study metabolic alternations caused by glucose and glutamine deprivation and uncover links between various fuel sources for highly and less invasive cancer cells. Our findings indicate that NAD+/NADH ratio regulates glutamine's direct effect on lactate production irrespective of the bioenergetic substrate requirement for different kinds of cancer cells. Our findings, using quantification of metabolites pertaining to central carbon and nitrogen metabolism provided clues as to which pathways relevant to glycolysis, the pentose phosphate pathway, the TCA, urea cycles and lipid cycles, amino acid and nucleotide metabolisms may be altered by glucose and glutamine in cancer cells. This resulted in identification of dominant factors which control cancer metabolism. We believe that development of our oncosecretomics based metabolic strategy provides an unprecedented opportunity for the development of nutritional supplementation that can deregulate the adaptations and alterations induced by various nutrients in cancer metabolism. Citation Format: Abhinav Achreja, Lifeng Yang, Hongyun Zhao, Juan C. Marini, Deepak Nagrath. Integrated energetics and flux analysis reveals differential metabolic reprogramming in highly and less invasive cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1892. doi:10.1158/1538-7445.AM2013-1892 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.