Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner.

Autor:	Meinert M; Department of Physiological Chemistry, University of Würzburg, Würzburg, Germany., Jessen C; Institute of Pathology, University of Würzburg, Würzburg, Germany., Hufnagel A; Institute of Pathology, University of Würzburg, Würzburg, Germany., Kreß JKC; Institute of Pathology, University of Würzburg, Würzburg, Germany., Burnworth M; Institute of Pathology, University of Würzburg, Würzburg, Germany., Däubler T; Institute of Pathology, University of Würzburg, Würzburg, Germany., Gallasch T; Institute of Pathology, University of Würzburg, Würzburg, Germany., Xavier da Silva TN; Rudolf-Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Dos Santos AF; Rudolf-Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Ade CP; Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany., Schmitz W; Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany., Kneitz S; Department of Biochemistry and Cell Biology, University of Würzburg, Würzburg, Germany., Friedmann Angeli JP; Rudolf-Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Meierjohann S; Department of Physiological Chemistry, University of Würzburg, Würzburg, Germany; Institute of Pathology, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany. Electronic address: svenja.meierjohann@uni-wuerzburg.de.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Apr; Vol. 70, pp. 103011. Date of Electronic Publication: 2023 Dec 27.
DOI:	10.1016/j.redox.2023.103011
Abstrakt:	The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf CA ; Pten lox/+ melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2. Competing Interests: Declaration of competing interest The authors report no declarations of interest. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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