title: Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism.
abstract: Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla CA 92093-0412, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Zielinski
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla CA 92093-0412, USA.|Institute of Engineering in Medicine, University of California, San Diego, La Jolla CA 92093-0412, USA.
authors.forename: Neema
authors.initials: N
authors.lastname: Jamshidi
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla CA 92093-0412, USA.
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Corbett
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla CA 92093-0412, USA.
authors.forename: Aarash
authors.initials: A
authors.lastname: Bordbar
authors.affiliation: Department of Bioinformatics and Systems Biology, University of California, San Diego, La Jolla CA 92093-0412, USA.|The Novo Nordisk Center for Biosustainability at the University of California San Diego School of Medicine, University of California, San Diego, La Jolla CA 92093-0412, USA.|Department of Pediatrics, University of California, San Diego, La Jolla CA 92093-0412, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla CA 92093-0412, USA.|Department of Pediatrics, University of California, San Diego, La Jolla CA 92093-0412, USA.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D018533:Biomass; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D064688:Metabolic Flux Analysis; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D014176:Protein Biosynthesis; D049490:Systems Biology / Q000379:methods*
chemical_list: D005973:Glutamine; D000255:Adenosine Triphosphate; D005947:Glucose