Quantification of the inputs and outputs of serine and glycine metabolism in cancer cells

Abstract

Background

The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.

Results

In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2 %, 24.0 %, and 5.7 %, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6 %), conversion from serine (45.1 %), and other sources (9.4 %). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7 %) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3 %) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100 %), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.

Conclusions

By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.