RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis
Mu-En Wang, … , Jiaoti Huang, Ming Chen
Mu-En Wang, … , Jiaoti Huang, Ming Chen
Published March 16, 2023
Citation Information: J Clin Invest. 2023;133(10):e166647. https://doi.org/10.1172/JCI166647.
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Research Article Oncology

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

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 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.

Authors

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

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Figure 4

Induction of ferroptosis suppresses the growth of RB-knockdown PC3 xenografts.

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Induction of ferroptosis suppresses the growth of RB-knockdown PC3 xenog...
(A–C) Tumor volume over the course of treatment (A), final tumor volume (B), or final tumor weight (C) of control or RB stable–knockdown PC3 xenografts after 4-week treatment with vehicle or JKE-1674. n = 5~6 mice per group. (D) H&E and IHC staining of control or RB stable–knockdown PC3 xenografts after 4-week treatment with vehicle or JKE-1674. Scale bars: 25 μm. (E–I) Body weight (E), the levels of plasma urea (F), alanine transaminase (ALT) (G), aspartate aminotransferase (AST) (H), and H&E staining of liver, kidney, and testis tissues (I) of nude mice after implantation of control or RB stable–knockdown PC3 xenografts and treatment with vehicle or JKE-1674 for 4 weeks. Scale bars: 25 μm. JKE-1674 was administered orally at a dose of 25 mg/kg body weight every other day. In A–C, 2-way ANOVA with Tukey’s multiple-comparison test was used to determine significance. In F–H, unpaired 2-tailed t test was used to determine significance. In A, the comparison between vehicle- and JKE-1674– treated RB stable–knockdown PC3 xenografts is shown. *P < 0.05, **P < 0.01, ***P < 0.001. ****P < 0.0001. Data are shown as the mean ± SD.