RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.
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2023-03
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Abstract
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.
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Wang, Mu-En, Jiaqi Chen, Yi Lu, Alyssa R Bawcom, Jinjin Wu, Jianhong Ou, John M Asara, Andrew J Armstrong, et al. (2023). RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. The Journal of clinical investigation. p. e166647. 10.1172/jci166647 Retrieved from https://hdl.handle.net/10161/27380.
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Scholars@Duke
Qianben Wang
Dr. Wang's laboratory is primarily focused on understanding the transcriptional and epigenetic mechanisms that drive the progression of hormone-dependent cancers. Additionally, they investigate the role of host proteases in coronavirus infection. Their recent studies aim to combine CRISPR/Cas13 technologies with nanotechnology to target undruggable transcription factors in cancers and host proteases for controlling infections caused by SARS-CoV-2 and related coronaviruses.
Ming Chen
Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long–term goal of developing new therapeutic strategies for preventing and treating metastatic disease.
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