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

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 R...

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Published inThe Journal of clinical investigation Vol. 133; no. 10; pp. 1 - 12
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 15.05.2023
Subjects
Acetyl coenzyme A synthetase
Androgens
Animals
Apoptosis
Arachidonic acid
Biomedical research
Cancer therapies
Castration
Cell activation
Cell cycle
Cell death
Cell Line
Coenzyme A Ligases - genetics
Coenzyme A Ligases - metabolism
Development and progression
E2F protein
Ferroptosis
Ferroptosis - genetics
Genes
Genetic aspects
Genetic engineering
Health aspects
Humans
Kinases
Lipid peroxidation
Lipids
Male
Malignancy
Metastases
Metastasis
Mice
Oncology
Phospholipids
Physiological aspects
Prostate cancer
Prostatic Neoplasms - pathology
Retinoblastoma
Retinoblastoma Binding Proteins - genetics
Retinoblastoma Binding Proteins - metabolism
Transcription factors
Tumor suppressor genes
Tumors
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
United States
Oncology
Prostate cancer
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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 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.
AbstractList 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 RBI-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 RBI-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 RBI-deficient malignancies.
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.
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 RBIdeficient 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 RBI-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 RBI-deficient malignancies.
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.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.
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.
Audience Academic
Author Huang, Jiaoti
Ou, Jianhong
Wu, Jinjin
Armstrong, Andrew J.
Wang, Qianben
Chen, Ming
Asara, John M.
Lu, Yi
Wang, Yuzhuo
Wang, Mu-En
Chen, Jiaqi
Li, Lei
Bawcom, Alyssa R.
AuthorAffiliation 9 Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada
8 Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
6 Department of Pharmacology and Cancer Biology, Department of Medicine, Division of Medical Oncology and Urology, Duke University School of Medicine, Durham, North Carolina, USA
1 Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
3 Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
4 Regeneration Center, Duke University, Durham, North Carolina, USA
2 Duke Cancer Institute, Duke University, Durham, North Carolina, USA
5 Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
7 Center for Prostate and Urologic Cancers, Duke Cancer Institute, Duke Universi
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36928314$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright COPYRIGHT 2023 American Society for Clinical Investigation
Copyright American Society for Clinical Investigation May 2023
2023 Wang et al. 2023 Wang et al.
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Prostate cancer
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Snippet Inactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate...
Inactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate...
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SubjectTerms Acetyl coenzyme A synthetase
Androgens
Animals
Apoptosis
Arachidonic acid
Biomedical research
Cancer therapies
Castration
Cell activation
Cell cycle
Cell death
Cell Line
Coenzyme A Ligases - genetics
Coenzyme A Ligases - metabolism
Development and progression
E2F protein
Ferroptosis
Ferroptosis - genetics
Genes
Genetic aspects
Genetic engineering
Health aspects
Humans
Kinases
Lipid peroxidation
Lipids
Male
Malignancy
Metastases
Metastasis
Mice
Oncology
Phospholipids
Physiological aspects
Prostate cancer
Prostatic Neoplasms - pathology
Retinoblastoma
Retinoblastoma Binding Proteins - genetics
Retinoblastoma Binding Proteins - metabolism
Transcription factors
Tumor suppressor genes
Tumors
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Title RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis
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