Metabolic re-wiring under glucose-limitation favours serine synthesis to support cancer cell survival

Metabolism is an interlinked series of biochemical reactions that support biosynthesis, bioenergetics and redox balance on a cellular and a systemic level. One key metabolic pathway for proliferation is the one-carbon (1C) metabolism which is well documented to be upregulated in many tumours. In 1C metabolism, the non-essential amino acid serine provides the 1C units needed for purine and pyrimidine biosynthesis. However, recent work by our group has shown that 1C metabolism is running in excess of the cell’s anabolic need. It was observed that the 1C units were excreted from cells as formate, suggesting additional potential roles of serine catabolism. Interestingly, when cancer cells were cultured in galactose to mimic glucose depletion, they upregulated serine catabolism and formate overflow, indicating that this pathway has also importance in bioenergetics and redox balance.
Using stable-isotope tracing, we were able to see that cancer cells cultured in 13C galactose favour redirecting glycolytic carbons toward serine synthesis rather than to pyruvate, indicating that serine synthesis has superior importance when carbon availability is limiting. Targeting serine synthesis in such conditions decreased the proliferative capacity and viability of cancer cells. In summary, this re-wired metabolism benefits the cell’s bioenergetics, biosynthesis and redox balance to maintain survival under these nutrient-stress conditions. It adds a novel aspect to the observation that targeting serine synthesis in tumours in vivo effectively delays tumour progression.

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