ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Pharmacologic Inhibition of EIF4A Blocks NRF2 Synthesis to Prevent Osteosarcoma Metastasis.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Spatially coordinated RTK-ERK signaling dynamics shape osteosarcoma single-cell drug response in the lung microenvironment.bioRxiv : the preprint server for biology · 2026Article
- Surface and global proteomics identify ROR2 and other proteins as potentially actionable immunotherapeutic targets in osteosarcoma.Cell reports · 2026Article
- Paediatric therapeutic development workshop on osteosarcoma.British journal of cancer · 2026Review
- Chondroitin sulfate shapes the unfolded protein response in osteosarcoma to sustain cancer cell survival during ER stress.Cell death & disease · 2026Article
- Omacetaxine reduces c-Myc expression and demonstrates antitumor effects in osteosarcoma.Scientific reports · 2026Article
- Wise as a Serpent and Gentle as a Dove: Pharmacological Targeting of NRF2/KEAP1 Pathway from Treasure Trove of Mother Nature.Drug design, development and therapy · 2026Review
- Therapeutic efficacy of oncolytic adenovirus YSCH-01 in osteosarcoma evaluated in PDX and CDX mouse models.Scientific reports · 2025Article
- Spatial Transcriptomics Reveals Transcriptomic and Immune Microenvironment Reprogramming during Thyroid Carcinoma Dedifferentiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Blocking NRF2 Translation by Inhibition of Cap-Dependent Initiation Sensitizes Lymphoma Cells to Ferroptosis and CAR T-cell Immunotherapy.Cancer research · 2025Article
- NRF2 promotes the migration of ovarian cancer cell lines by targeting TAGLN mediated epithelial-mesenchymal transition.Journal of ovarian research · 2025Article
- Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies.Cancers · 2025Review
- eIF4F-mediated dysregulation of mRNA translation in cancer.RNA (New York, N.Y.) · 2025Review
- Eukaryotic initiation factors: central factor associating mRNA translational plasticity during neuropathic pain progression.Frontiers in neurology · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
purposeEffective therapies for metastatic osteosarcoma (OS) remain a critical unmet need. Targeting mRNA translation in metastatic OS offers a promising option, as selective translation drives the synthesis of cytoprotective proteins under harsh microenvironmental conditions to facilitate metastatic competence. EXPERIMENTAL
designWe assessed the expression levels of eukaryotic translation factors in OS, revealing the high expression of the eukaryotic initiation factor 4A1 (EIF4A1). Using a panel of metastatic OS cell lines and patient-derived xenograft (PDX) models, EIF4A1 inhibitors were evaluated for their ability to block proliferation and reduce survival under oxidative stress, mimicking harsh conditions of the lung microenvironment. Inhibitors were also evaluated for their antimetastatic activity using the ex vivo pulmonary metastasis assay and in vivo metastasis models. Proteomics was performed to catalog which cytoprotective proteins or pathways were affected by EIF4A1 inhibition.
resultsCR-1-31B, a rocaglate-based EIF4A1 inhibitor, exhibited nanomolar cytotoxicity against all metastatic OS models tested. CR-1-31B exacerbated oxidative stress and apoptosis when OS cells were co-treated with tert-butylhydroquinone, a chemical oxidative stress inducer. CR-1-31B potently inhibited OS growth in the pulmonary metastasis assay model and in experimental and spontaneous models of OS lung metastasis. Proteomic analysis revealed that tert-butylhydroquinone-mediated upregulation of the NRF2 antioxidant factor was blocked by co-treatment with CR-1-31B. Genetic inactivation of NRF2 phenocopied the antimetastatic activity of CR-1-31B. Finally, the clinical-grade EIF4A1 phase-1-to-2 inhibitor, zotatifin, similarly blocked NRF2 synthesis and the OS metastatic phenotype.
conclusionsCollectively, our data reveal that pharmacologic targeting of EIF4A1 is highly effective in blocking OS metastasis by blunting the NRF2 antioxidant response.
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