Abstract SY26-01: Mitochondrial metabolism in the survival and growth of cancer cells
Authors: DeBerardinis Ralph J. 
Published: June 2012

Abstract
Interest in tumor metabolism stems from the assumption that metabolic differences between normal and malignant cells can be exploited to improve imaging, therapy and clinical outcomes in cancer patients. Mutations in tumor suppressors and oncogenes influence nutrient utilization in cancer cells, presumably to allow malignant cells to meet the metabolic demands of survival, growth and proliferation. Many of these effects converge on glucose utilization, reinforcing the notion first proposed by Otto Warburg that malignant cells have high rates of glycolysis but suppressed or impaired mitochondrial metabolism (the “Warburg effect”). However this simple model fails to explain the most fundamental property of cancer cells: their uncontrolled growth in culture and in vivo. Cell growth requires an abundant supply of macromolecular precursors, and many of these key molecules are formed as byproducts of mitochondrial metabolism. Thus, a more realistic alternative to Warburg's model is that the high glycolytic flux observed in tumor cells must be complemented by mitochondrial systems optimized to generate precursors for biosynthesis; the former pathway helps maintain cellular bioenergetics and the latter pathways support maximal cell growth and proliferation. We used metabolic flux analysis to determine the effects of oncogenic signaling on glycolysis and mitochondrial metabolism in normal human diploid cells. The data demonstrate that oncogenes and enhanced growth factor signaling stimulate the delivery of carbon from glucose and other nutrients into pools of mitochondrial metabolites. The effects on these mitochondrial activities are even more dramatic than the effects on glycolysis, implying that enhanced mitochondrial fluxes are essential components of malignant transformation. We identified three distinct modes of mitochondrial metabolism that differed from each other by the allocation of carbon from glucose and glutamine into specific mitochondrial pathways. Strikingly, the choice of pathway used to supply carbon to the tricarboxylic acid (TCA) cycle determines cellular sensitivity to perturbations of glucose and glutamine metabolism in vitro and in vivo. We applied similar methods in flux analysis to interrogate the metabolism in situ of brain tumors in mice and humans. These studies confirmed the presence of robust mitochondrial activity, along with the Warburg effect, in all tumors analyzed. In particular, all tumors used the TCA cycle and other mitochondrial pathways to produce macromolecular precursors from glucose and/or glutamine. Together, the findings underscore the importance and complexity of mitochondrial metabolism in tumor cell growth. They also emphasize the feasibility of using stable isotope infusions to obtain metabolic information directly from intact tumors in human patients and mouse models of cancer, rather than relying exclusively on the behavior of tumor cell lines in culture. We anticipate that studies like these will provide an accurate picture of the metabolic basis of tumor cell growth, and will support the rational design of novel metabolic strategies to image and treat cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY26-01. doi:10.1158/1538-7445.AM2011-SY26-01