RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.
| dc.contributor.author | Wang, Mu-En | |
| dc.contributor.author | Chen, Jiaqi | |
| dc.contributor.author | Lu, Yi | |
| dc.contributor.author | Bawcom, Alyssa R | |
| dc.contributor.author | Wu, Jinjin | |
| dc.contributor.author | Ou, Jianhong | |
| dc.contributor.author | Asara, John M | |
| dc.contributor.author | Armstrong, Andrew J | |
| dc.contributor.author | Wang, Qianben | |
| dc.contributor.author | Li, Lei | |
| dc.contributor.author | Wang, Yuzhuo | |
| dc.contributor.author | Huang, Jiaoti | |
| dc.contributor.author | Chen, Ming | |
| dc.date.accessioned | 2023-05-15T16:22:00Z | |
| dc.date.available | 2023-05-15T16:22:00Z | |
| dc.date.issued | 2023-03 | |
| dc.date.updated | 2023-05-15T16:21:59Z | |
| dc.description.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. | |
| dc.identifier | 166647 | |
| dc.identifier.issn | 0021-9738 | |
| dc.identifier.issn | 1558-8238 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | American Society for Clinical Investigation | |
| dc.relation.ispartof | The Journal of clinical investigation | |
| dc.relation.isversionof | 10.1172/jci166647 | |
| dc.subject | Oncology | |
| dc.subject | Prostate cancer | |
| dc.title | RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Armstrong, Andrew J|0000-0001-7012-1754 | |
| duke.contributor.orcid | Wang, Qianben|0000-0003-2636-7145 | |
| duke.contributor.orcid | Huang, Jiaoti|0000-0003-1195-1998 | |
| duke.contributor.orcid | Chen, Ming|0000-0002-3470-1062 | |
| pubs.begin-page | e166647 | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Cell Biology | |
| pubs.organisational-group | Pharmacology & Cancer Biology | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Pathology | |
| pubs.organisational-group | Surgery | |
| pubs.organisational-group | Medicine, Medical Oncology | |
| pubs.organisational-group | Surgery, Urology | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.publication-status | Published |
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