2. Academic Validation
  3. Breast cancer cells have an increased ferroptosis risk induced by system xc- blockade after deliberately downregulating CYTL1 to mediate malignancy

Breast cancer cells have an increased ferroptosis risk induced by system xc- blockade after deliberately downregulating CYTL1 to mediate malignancy

  • Redox Biol. 2024 Apr:70:103034. doi: 10.1016/j.redox.2024.103034.
Wenwen Xue 1,  Ying Yu 1,  Yongzhong Yao 2,  Lin Zhou 1,  Ying Huang 1,  Yixuan Wang 1,  Zhixiu Chen 1,  Liwei Wang 1,  Xinran Li 3,  Xiaoning Wang 1,  Ronghui Du 4,  Yan Shen 5,  Qiang Xu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China.
  • 2 Department of Breast Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: [email protected].
PMID: 38211443 DOI: 10.1016/j.redox.2024.103034
Abstract

Cytokine-like protein 1 (CYTL1) expression is deliberately downregulated during the progression of multiple types of cancers, especially breast Cancer. However, the metabolic characteristics of Cancer progression remain unclear. Here, we uncovered a risk of breast Cancer cells harboring low CYTL1 expression, which is metabolically controlled during malignant progression. We performed metabolism comparison and revealed that breast Cancer cells with low CYTL1 expression have highly suppressed transsulfuration activity that is driven by cystathionine β-synthase (CBS) and contributes to de novo cysteine synthesis. Mechanistically, CYTL1 activated Nrf2 by promoting autophagic Keap1 degradation, and Nrf2 subsequently transactivated CBS expression. Due to the lack of cellular cysteine synthesis, breast Cancer cells with low CYTL1 expression showed hypersensitivity to system xc- blockade-induced Ferroptosis in vitro and in vivo. Silencing CBS counteracted CYTL1-mediated Ferroptosis resistance. Our results show the importance of exogeneous cysteine in breast Cancer cells with low CYTL1 expression and highlight a potential metabolic vulnerability to target.

Keywords

Breast cancer; CBS; CYTL1; Ferroptosis; Transsulfuration pathway.

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