Cell Metabolism
Volume 30, Issue 5, 5 November 2019, Pages 865-876.e5
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Article
Transsulfuration Activity Can Support Cell Growth upon Extracellular Cysteine Limitation

https://doi.org/10.1016/j.cmet.2019.09.009Get rights and content
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Highlights

  • Transsulfuration contributes to de novo cysteine synthesis in cancer cells

  • Transsulfuration pathway enzymes are regulated by the GCN2-ATF4 axis

  • The rate of transsulfuration activity is determined by SAM to SAH conversion

  • Transsulfuration supports cancer cell growth upon extracellular cysteine limitation

Summary

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.

Keywords

cysteine
redox homeostasis
metabolism
cancer
transsulfuration
xCT
glutathione
methylation

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