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, however, 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.
The Journal of clinical investigation. 2023 Mar 16 [Epub ahead of print]
Mu-En Wang, Jiaqi Chen, Yi Lu, Alyssa R Bawcom, Jinjin Wu, Jianhong Ou, John M Asara, Andrew J Armstrong, Qianben Wang, Lei Li, Yuzhuo Wang, Jiaoti Huang, Ming Chen
Department of Pathology, Duke University School of Medicine, Durham, United States of America., Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Department of Pathology, Duke Univeristy School of Medicine, Durham, United States of America., Regeneration Center, Duke University, durham, United States of America., Division of Signal Transduction, Beth Isreal Deaconess Medical Center, Boston, United States of America., Department of Medicine, Division of Medical Oncology and Urology, Duke University, Durham, United States of America., Department of Urologic Sciences, The University of British Columbia, Vancouver, Canada.