Browsing by Author "Ou, Jianhong"

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    RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.
    (The Journal of clinical investigation, 2023-03) 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
    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.