TY  - JOUR
A1  - Meinert, Madlen
A1  - Jessen, Christina
A1  - Hufnagel, Anita
A1  - Kreß, Julia Katharina Charlotte
A1  - Burnworth, Mychal
A1  - Däubler, Theo
A1  - Gallasch, Till
A1  - Da Xavier Silva, Thamara Nishida
A1  - Dos Santos, Ancély Ferreira
A1  - Ade, Carsten Patrick
A1  - Schmitz, Werner
A1  - Kneitz, Susanne
A1  - Friedmann Angeli, José Pedro
A1  - Meierjohann, Svenja
T1  - Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner
JF  - Redox Biology
N2  - 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.
KW  - thiol starvation
KW  - ATF4
KW  - NRF2
KW  - melanoma
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350328
VL  - 70
ER  -