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

• Published in: The Journal of clinical investigation Vol. 133; no. 10; pp. 1 - 12
• Main Authors: Wang, Mu-En, Chen, Jiaqi, Lu, Yi, Bawcom, Alyssa R., Wu, Jinjin, Ou, Jianhong, Asara, John M., Armstrong, Andrew J., Wang, Qianben, Li, Lei, Wang, Yuzhuo, Huang, Jiaoti, Chen, Ming
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.05.2023
• Subjects: Acetyl coenzyme A synthetase; Androgens; Animals; Apoptosis; Arachidonic acid; Biomedical research; Cancer therapies; Castration; Cell activation; Cell cycle; Cell death; Cell Line; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Development and progression; E2F protein; Ferroptosis; Ferroptosis - genetics; Genes; Genetic aspects; Genetic engineering; Health aspects; Humans; Kinases; Lipid peroxidation; Lipids; Male; Malignancy; Metastases; Metastasis; Mice; Oncology; Phospholipids; Physiological aspects; Prostate cancer; Prostatic Neoplasms - pathology; Retinoblastoma; Retinoblastoma Binding Proteins - genetics; Retinoblastoma Binding Proteins - metabolism; Transcription factors; Tumor suppressor genes; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; United States; Oncology; Prostate cancer
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI166647

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.