Dissecting cellular metabolism during the cell cycle

N. SCAGLIA; S. TYEKUCHEVA; C. PHOTOPOULOS; M. LODA

Otro; HMS Pathology Annual Retreat; 2012

Although the intricate network of signals that initiates and drives cell cycle progression has been intensely studied, much less is known about the cellular metabolic needs during different phases of the cell cycle and how the cells fulfill those requirements. The objective of this project is to dissect the metabolic changes occurring throughout the mammalian cell cycle. The study focuses mainly on 3 pathways that are important for proliferation and survival in cancer cells: de novo fatty acid synthesis, glycolysis, and glutaminolysis. A metabolic profile showed that ~25% of the analyzed metabolites change across the cell cycle in HeLa cells synchronized by double thymidine block. Among the pathways more represented were the polyamine metabolism (proof of principle), glycolysis, phospholipid metabolism and nucleotides. The metabolites levels, together with radiotracer experiments, showed that there's an increase in phosphatidylcholine and de novo fatty acid synthesis as the cells go from G2/M to G1 phase. The inhibition of fatty acid synthesis blocks the cell cycle at G2/M phase, suggesting that the cells require membrane synthesis to complete cell division. Given that the synthesis in this moment of the cycle is not related to cellular growth, it's possible that the cells use these phospholipids to reassemble the nuclear membrane or to provide extra membrane surface required for cytokinesis. Taken together, these results show a metabolic reprogramming during the cell cycle and provide the groundwork for testing whether a combined approach, targeting the cell cycle and specific metabolic pathways, is beneficial for cancer therapy.