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

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.
AuthorsWenwen Xue, Ying Yu, Yongzhong Yao, Lin Zhou, Ying Huang, Yixuan Wang, Zhixiu Chen, Liwei Wang, Xinran Li, Xiaoning Wang, Ronghui Du, Yan Shen, Qiang Xu
JournalRedox biology (Redox Biol) Vol. 70 Pg. 103034 (Apr 2024) ISSN: 2213-2317 [Electronic] Netherlands
PMID38211443 (Publication Type: Journal Article)
CopyrightCopyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Cysteine
  • Cystathionine beta-Synthase
  • CYTL1 protein, human
  • Blood Proteins
  • Cytokines
Topics
  • Humans
  • Female
  • Kelch-Like ECH-Associated Protein 1 (metabolism)
  • Breast Neoplasms (genetics)
  • Ferroptosis
  • NF-E2-Related Factor 2 (genetics, metabolism)
  • Cysteine
  • Cystathionine beta-Synthase (metabolism)
  • Blood Proteins (metabolism)
  • Cytokines (metabolism)

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