三阴性乳腺癌
生物
胱氨酸
癌症研究
谷胱甘肽
氧化应激
下调和上调
转录因子
细胞生物学
半胱氨酸
乳腺癌
癌症
生物化学
基因
遗传学
酶
作者
Laura Bottoni,Alberto E. Minetti,Giulia Realini,Elena Pio,Daniela Giustarini,Ranieri Rossi,Chiara Rocchio,Lorenzo Franci,Laura Salvini,Orazio Catona,Romina D’Aurizio,Seyed Mohammad Mahdi Rasa,Emanuele Giurisato,Francesco Neri,Maurizio Orlandini,Mario Chiariello,Federico Galvagni
出处
期刊:Oncogene
[Springer Nature]
日期:2024-04-10
标识
DOI:10.1038/s41388-024-03025-0
摘要
Triple-negative breast cancer (TNBC) is a very aggressive and heterogeneous group of tumors. In order to develop effective therapeutic strategies, it is therefore essential to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy. TNBC cells are highly dependent on exogenous cystine, provided by overexpression of the cystine/glutamate antiporter SLC7A11/xCT, to fuel glutathione synthesis and promote an oxidative stress response consistent with their high metabolic demands. Here we show that TNBC cells of the mesenchymal stem-like subtype (MSL) utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to defend against oxidative stress. Mechanistically, we demonstrate that NRF2 activation is mediated by direct cysteinylation of the inhibitor KEAP1. Furthermore, we show that cystine-mediated NRF2 activation induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Remarkably, in survival analysis, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, expression of exogenous OSGIN1, similarly to expression of exogenous NRF2, can prevent cystine depletion-dependent death of MSL TNBC cells. The results suggest that the cystine/NRF2/OSGIN1 axis is a potential target for effective treatment of MSL TNBCs.
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