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Title: SU-E-J-102: Separation of Metabolic Supply and Demand: From Power Grid Economics to Cancer Metabolism

Purpose: To study a new model of glucose metabolism which is primarily governed by the timescale of the energetic demand and not by the oxygen level, and its implication on cancer metabolism (Warburg effect) Methods: 1) Metabolic profiling of membrane transporters activity in several cell lines, which represent the spectrum from normal breast epithelium to aggressive, metastatic cancer, using Seahorse XF reader.2) Spatial localization of oxidative and non-oxidative metabolic components using immunocytochemical imaging of the glycolytic ATP-producing enzyme, pyruvate kinase and mitochondria. 3) Finite element simulations of coupled partial differential equations using COMSOL and MATLAB. Results: Inhibition or activation of pumps on the cell membrane led to reduction or increase in aerobic glycolysis, respectively, while oxidative phosphorylation remained unchanged. These results were consistent with computational simulations of changes in short-timescale demand for energy by cell membrane processes. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. These predictions were confirmed experimentally. Conclusion: The results in this work support a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Similar tomore » power grid economics, optimal metabolic control requires the two pathways, even in normoxic conditions, to match two different types of energy demands. Cells use aerobic metabolism to meet baseline, steady energy demand and glycolytic metabolism to meet short-timescale energy demands, mainly from membrane transport activities, even in the presence of oxygen. This model provides a mechanism for the origin of the Warburg effect in cancer cells. Here, the Warburg effect emerges during carcinogenesis is a physiological response to an increase in energy demands from membrane transporters, required for cell division, growth, and migration. This work is supported by the NIH Physical Sciences in Oncology Center grant 1U54CA143970-03 and NIH R01 CA077575-10.« less
Authors:
; ; ;  [1]
  1. Moffitt Cancer Center and Research Institute, Tampa, FL (United States)
Publication Date:
OSTI Identifier:
22325256
Resource Type:
Journal Article
Resource Relation:
Journal Name: Medical Physics; Journal Volume: 41; Journal Issue: 6; Other Information: (c) 2014 American Association of Physicists in Medicine; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; CARCINOGENESIS; CELL DIVISION; CELL MEMBRANES; ENZYMES; EPITHELIUM; FINITE ELEMENT METHOD; GLUCOSE; GLYCOLYSIS; MAMMARY GLANDS; MEMBRANE TRANSPORT; MITOCHONDRIA; NEOPLASMS; OXIDATION; PHOSPHORYLATION; SPATIAL DISTRIBUTION; SUPPLY AND DEMAND