JCB-JEM Symposium: Lewis Cantley - PI 3-Kinase and Cancer Metabolism
27Lewis Cantley gives his talk "PI 3-Kinase and Cancer Metabolism" as part of the JCB-JEM symposium on Tackling Cancer Plasticity and Heterogeneity at The Rockefeller University in New York, October 9th, 2018. https://rupress.org/pages/jcb-jem-symposium-tackling-cancer-plasticity-and-heterogeneity
The Cantley lab at Weill Cornell Medicine College studies the regulation of metabolism in cancer.
Methotrexate is a chemotherapy agent used to treat many diseases, including cancer. In this talk, Cantley describes how the cellular folate pool was radioactively labelled and analyzed by HPLC in order to quantify folate metabolites in triple-negative breast cancer cells in response to methotrexate treatment. The study shows that the mitochondrial folate pathway converts serine to glycine and formate, and this formate is required for the generation of formyl-THF in the cytosol. Disruption of the mitochondrial THF pathway results in degradation of cytosolic THF to para-amino benzoyl-glutamate (pABG) that is then acetylated by NAT1 to generate pAcABG. Treatment of cells with methotrexate causes rapid accumulation of pAcABG and a decline in cytosolic folates, which likely contributes to the effectiveness of methotrexate in treating certain cancers, especially cancers with high levels of reactive oxygen species (ROS). pAcABG is stable and becomes more abundant than other folate species under conditions of high ROS and low formate or in the presence of methotrexate. QDPR also acts as a protector of THF from oxidative damage, thus preserving the folate pool in cells.
Video © Rockefeller University Press