Flux Balance Analysis Identifies Distinct NADPH Production Strategies Across NCI 60 Cancer Cell Lines

Flux Balance Analysis is a linear mathematical procedure which determines the set of reaction fluxes to produce a maximum flux of a reaction of interest. In this study, a core cancer model developed by Zielinski et al. 2017 is constrained by a set of 59 cancer cell type specific uptake and secretion rates. Optimizing for cell type specific biomass objective reactions and examining serine flux distributions reveals variability in production of NADPH. In many cell lines, production of NADPH is correlated to biosynthetic demand, however, outliers exist that produce excess NADPH beyond that of biomass demand. These outliers are first characterized by their NADPH production strategy (pentose phosphate pathway or a combination of One Folate Cycle and Malic Enzyme) and then the factors responsible for the different NADPH production strategies are identified. Results indicate that pentose phosphate pathway (PPP) producing NADPH cell lines had reprogrammed tricarboxylic acid cycle metabolism to meet the demand for decreased flux through glycolytic enzymes, while one folate cycle and malic enzyme (OFC + ME) producing NADPH cell lines had higher threonine, tyrosine and serine uptake.