Transsulfuration Activity Can Support Cell Growth upon Extracellular Cysteine Limitation

Cysteine acts both as a building unit for protein translation and as the limiting substrate for glutathione synthesis to support the cellular antioxidant system. In addition to transporter-mediated uptake, cellular cysteine can also be synthesized from methionine through the transsulfuration pathway. Here, we investigate the regulation of transsulfuration and its role in sustaining cell proliferation upon extracellular cysteine limitation, a condition reported to occur in human tumors as they grow in size. We observed constitutive expression of transsulfuration enzymes in a subset of cancer cell lines, while in other cells, these enzymes are induced following cysteine deprivation. We show that both constitutive and inducible transsulfuration activities contribute to the cellular cysteine pool and redox homeostasis. The rate of transsulfuration is determined by the cellular capacity to conduct methylation reactions that convert S-adenosylmethionine to S-adenosylhomocysteine. Finally, our results demonstrate that transsulfuration-mediated cysteine synthesis is critical in promoting tumor growth in vivo.