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RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.

Publication ,  Journal Article
Wang, M-E; Chen, J; Lu, Y; Bawcom, AR; Wu, J; Ou, J; Asara, JM; Armstrong, AJ; Wang, Q; Li, L; Wang, Y; Huang, J; Chen, M
Published in: J Clin Invest
May 15, 2023

Inactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate cancer, and predicts poor clinical outcomes. Effective therapeutic strategies against RB1-deficient cancers remain elusive. Here, we showed that RB1 loss/E2F activation sensitized cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, by upregulating expression of ACSL4 and enriching ACSL4-dependent arachidonic acid-containing phospholipids, which are key components of ferroptosis execution. ACSL4 appeared to be a direct E2F target gene and was critical to RB1 loss-induced sensitization to ferroptosis. Importantly, using cell line-derived xenografts and genetically engineered tumor models, we demonstrated that induction of ferroptosis in vivo by JKE-1674, a highly selective and stable GPX4 inhibitor, blocked RB1-deficient prostate tumor growth and metastasis and led to improved survival of the mice. Thus, our findings uncover an RB/E2F/ACSL4 molecular axis that governs ferroptosis and also suggest a promising approach for the treatment of RB1-deficient malignancies.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 15, 2023

Volume

133

Issue

10

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Retinoblastoma Binding Proteins
  • Prostatic Neoplasms
  • Mice
  • Male
  • Immunology
  • Humans
  • Ferroptosis
  • Coenzyme A Ligases
  • Cell Line
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, M.-E., Chen, J., Lu, Y., Bawcom, A. R., Wu, J., Ou, J., … Chen, M. (2023). RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. J Clin Invest, 133(10). https://doi.org/10.1172/JCI166647
Wang, Mu-En, Jiaqi Chen, Yi Lu, Alyssa R. Bawcom, Jinjin Wu, Jianhong Ou, John M. Asara, et al. “RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.J Clin Invest 133, no. 10 (May 15, 2023). https://doi.org/10.1172/JCI166647.
Wang M-E, Chen J, Lu Y, Bawcom AR, Wu J, Ou J, et al. RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. J Clin Invest. 2023 May 15;133(10).
Wang, Mu-En, et al. “RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.J Clin Invest, vol. 133, no. 10, May 2023. Pubmed, doi:10.1172/JCI166647.
Wang M-E, Chen J, Lu Y, Bawcom AR, Wu J, Ou J, Asara JM, Armstrong AJ, Wang Q, Li L, Wang Y, Huang J, Chen M. RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. J Clin Invest. 2023 May 15;133(10).

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 15, 2023

Volume

133

Issue

10

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Retinoblastoma Binding Proteins
  • Prostatic Neoplasms
  • Mice
  • Male
  • Immunology
  • Humans
  • Ferroptosis
  • Coenzyme A Ligases
  • Cell Line