title: The Warburg effect: a balance of flux analysis.
abstract: Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.
authors.affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine Diabetes Center, Bronx, New York, USA.
authors.forename: B
authors.initials: B
authors.lastname: Vaitheesvaran
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, Caligornia, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Division of Endocrinology and Metabolism, University of California, Los Angeles, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yee
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Q-Y
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Go
authors.affiliation: Functional Genomics/Proteomics Laboratories Creighton University medical Center, Nebraska, and School of Pharmaceutical Science and Technology at Dalian University of Technology, Dalian, China.
authors.forename: G G
authors.initials: GG
authors.lastname: Xiao
authors.affiliation: LA Biomedical Research Institute, Torrance, CA, USA and Department of Pediatrics, Division of Endocrinology and Metabolism, University of California, Los Angeles, California USA.
authors.forename: W N
authors.initials: WN
authors.lastname: Lee