Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.

Cysteine, a thiol-containing amino acid, is crucial for the synthesis of sulfur-containing biomolecules that control multiple essential cellular activities. Altered cysteine metabolism has been linked to numerous driver oncoproteins and tumor suppressors, as well as to malignant traits in cancer. Cysteine can be acquired from extracellular sources or synthesized de novo via the transsulfuration (TSS) pathway. Limited availability of cystine in tumor interstitial fluids raises the possible dependency on de novo cysteine synthesis via TSS. However, the contribution of TSS to cancer metabolism remains highly contentious. Based on recent findings, we provide new perspectives on this crucial but understudied metabolic pathway in cancer. • Cysteine is critical for synthesis of sulfur-containing biomolecules that control essential cellular activities, such as redox homeostasis, mitochondrial electron transport chain reactions, and the mRNA translation machinery. • During oncogenesis, cystine uptake by the xCT transporter is controlled by driver oncoproteins and tumor suppressors. However, cyst(e)ine levels are limited in tumor interstitial fluids, creating a potential dependency on de novo cysteine synthesis via the transsulfuration (TSS) pathway. • The contribution of de novo cysteine synthesis in cancer cells is highly contentious. • Novel rate-limiting factors for the TSS pathway and glutathione (GSH)-independent cytoprotective mechanisms have been identified in cancer cells under cystine deprivation. • De novo cysteine synthesis is likely a transient but highly plastic emergency stress response mechanism in cancer cells that encounter intermittent cystine deficiency in vivo. [ABSTRACT FROM AUTHOR]