Metabolic adaptations in proliferating cells and cancer

Abstract

The studies described in this dissertation focus on metabolic adaptations that occur during cell proliferation. In the first part of the thesis we focus on the Warburg effect which is a major hallmark of proliferating cells. We provide evidence that increased glucose consumption in proliferating cells requires malate dehydrogenase 1 (MDH1) to help regenerate the NAD required to sustain high levels of glycolysis. This NAD regeneration has previously only been attributed to lactate dehydrogenase (LDH). We found LDH was dispensable for proliferation whereas MDH1 was not. We also report the MDH1 gene is amplified in a significant number of human tumors and correlates with poor prognosis. We go on to show glutamine, not glucose is a carbon source for MDH1 during proliferation, which allows more of the glucose carbon consumed to go toward biomass production. The second part of the thesis focuses on glutamine metabolism. The increased consumption and metabolism of glutamine leads to increased cellular concentrations of alpha-ketoglutarate (αKG) a tumor suppressor metabolite that affects gene expression via non-metabolic co-factor functions. One of these functions is the activation of the cytosine demethylase, Tet. Increased αKG concentrations therefore change the tumor cell’s epigenetic landscape which can cause differentiation and growth arrest. We reasoned cancer cells must have mechanisms in place to prevent the tumor suppressor activity of αKG. We demonstrate that over-expression of the one carbon metabolism pathway which generates methyl groups and the cytosine methyl-transferase, DNMT1 provide an αKG resistance mechanism. We find combining αKG treatment with low concentrations of the DNMT1 inhibitor decitabine causes significant cell death and reveals a potential therapeutic vulnerability in glutamine addicted cancers. Taken together, our studies provide significant insight into the general biology of proliferative metabolism. Through these insights, our work opens new avenues for targeting the energy and biomass producing pathways cancer cells depend on to proliferate.