Metabolic alteration and their regulation during drug treatment in mammalian cancer cells
Final Report Abstract
In the process of malignant transformation, cells adapt their metabolism to their energy and biomass requirement to sustain uncontrolled proliferation. Important thereby are the metabolic processes of cen- tral carbon metabolism, which provide energy equivalents and biomass building blocks. The two major carbon sources fueling central carbon metabolism are glucose and glutamine, which can be converted via various pathways. Yet, in the _ght against cancer we hardly take any advantage of the di_eren- tial metabolism found in transformed versus non transformed cell. My main research projects were both focussed on elucidating cancer cell metabolism, thereby I speci_cally focused on the metabolic alteration and their regulation during drug treatment in mammalian cancer cells. In the _rst project I investigated the metabolic alterations triggered by the drug metformin and their implications for combinatorial drug therapy. In the second project I elucidated the regulatory events, which trigger the global switch in glutamine metabolism that is observed in growth conditions impairing or altering mitochondrial metabolism, such as hypoxia or metformin treatment. Metformin has anti-proliferative e_ects on cancer cells and cancer patients taking this anti-diabetic drug have improved survival, but the mechanism by which metformin improves cancer outcomes re- mains controversial. To explore a potential direct e_ect of metformin on cancer cells, we analyzed how metformin alters the metabolism of prostate cancer cells and tumors. We _nd that metformin decreases glucose oxidation and increases dependency on reductive glutamine metabolism in both prostate cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine metabolism in the presence of metformin further attenuates proliferation while increasing glutamine metabolism rescues the prolif- erative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer. Reductively metabolized glutamine is a major carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here, we identify several conditions where the _-ketoglutarate/citrate ratio is changed due to altered acetyl-CoA to citrate conversion, and demonstrate that reductive glutamine metabolism is initiated in response to any perturbation that results in an increase in the _-ketoglutarate/citrate ratio. Thus, changes in carbon source selection for fatty acid synthesis are a consequence of any alteration in the metabolic network caused by physiological or pharmacological interventions that changes this ratio in cells.
Publications
- Reductive Glutamine Utilization is a function of the mass action kinetics betweenα-ketoglutatrate and citrate. Cell Symposium - Hallmarks of Cancer; San Francisco; 2012
Fendt, S.-M.; Bell, E.; Keibler, M.A.; Mayers, J.; Vander Heiden, M.; and Stephanopoulos, G.
- Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway. Endocrine- Related Cancer; 2012, 19, 557–574
Hvid, H.; Fendt, S.-M.; Blouin, M.-J.; Birman, E.; Voisin, G.; Manegold Svendsen, A.; Frank, R.; Vander Heiden, M. G.; Stephanopoulos, G.; Falck Hansen, B. and Pollak, M
- Metformin deploys its antiprostate-cancer effect by suppressing glucose derived fatty acid production. International Conference on Systems Biology; Heidelberg; 2011
Fendt, S.-M.; Wirth, J.G.; Olumi, A.; and Stephanopoulos, G.
- Metformin shifts cellular metabolism towards glucose fermentation and dramatically increases glutamine fueling of tricarboxylic acid cycle metabolites and fatty acids. AACR - Metabolism and Cancer; Baltimore; 2011
Fendt, S.-M.; Wirth, J.G.; Keibler, M.A.; Olumi, A.; and Stephanopoulos, G.
- Expanding the concepts and tools of metabolic engineering to elucidate cancer metabolism. Biotechnology Progress; 2012, 28(6), 1409-1418
Keibler, M. A.; Fendt, S.-M. and Stephanopoulos, G.
- Reductive Glutamine Utilization is a function of the α-ketoglutarate to citrate ratio. DKFZ - Metabolism ’From Signalling to Disease’; Heidelberg; 2012
Fendt, S.-M.; Bell, E.; Keibler, M.A.; Mayers, J.; Wasylenko, T.; Vander Heiden, M.; and Stephanopoulos, G.
