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-limitation, they upregulated serine
catabolism and formate overflow, indicating that this pathway has also importance in bioenergetics
and redox balance.
Using stable-isotope tracing, we observed that cancer cells cultured under glucose-limitation favour
redirecting glycolytic carbons toward serine de novo 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.
Moreover, by using different genetic modifications of different 1C metabolism enzymes, we were
able to observe that under glucose-limitation serine synthesis pathway plays a role in biosynthesis,
bioenergetics and redox balance. Furthermore, when faced with glucose-limitation cancer cells re-
wire glutamine metabolism also towards supporting serine de novo synthesis showcasing the
metabolic flexibility of cancer cells.
In summary, by culturing cancer cells under glucose-limitation we were able to uncover their intrinsic
metabolic flexibility and plasticity to re-wire their metabolism towards serine synthesis. Additionally,
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.
Keywords: cancer metabolism/One-carbon metabolism/serine/glucose-limitation