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Small molecule inhibitors of eIF4A1/2 impair the oxidative stress response in osteosarcoma cells to block tumor growth and metastatic capacity

ABSTRACT: Effective therapies for metastatic osteosarcoma (OS) remain a major clinical unmet need. Targeting mRNA translation in metastatic OS represents an attractive option, as selective translation under stress supports the rapid synthesis of cytoprotective proteins that facilitate metastatic competence. We therefore assessed eukaryotic translation factors in OS, revealing high expression of eIF4A1 in metastatic OS. The eIF4A1 inhibitor, CR-1-31B, potently inhibited metastatic OS growth in vitro and reduced lung tumor burden in orthotopic mouse models. CR-1-31B synergized with the oxidative stress inducer, tert-butylhydroquinone (tBHQ), to enhance cell death under oxidative stress. Proteomic analysis revealed a subset of proteins that were upregulated by tBHQ alone, but inhibited by co-treatment of CR-1-31B, most notably the NRF2 antioxidant transcription factor, and NRF2 inactivation phenocopied CR-1-31B in blocking OS lung metastasis in vivo. Collectively, our data reveal that targeting eIF4A1 with CR-1-31B is highly effective in blocking OS metastasis by blunting the NRF2 antioxidant response.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bone Marrow

SUBMITTER: Christopher Hughes

LAB HEAD: Poul Sorensen

PROVIDER: PXD047420 | Pride | 2024-07-16

REPOSITORIES: Pride

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			Action	DRS
	ch_20220703_mikeCr131bProteome_cr2_rep1_diaHigh.raw	Raw
	ch_20220703_mikeCr131bProteome_cr2_rep1_diaLow.raw	Raw
	ch_20220703_mikeCr131bProteome_cr2_rep2_diaHigh.raw	Raw
	ch_20220703_mikeCr131bProteome_cr2_rep2_diaLow.raw	Raw
	ch_20220703_mikeCr131bProteome_cr2_rep3_diaHigh.raw	Raw

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Small molecule inhibitors of eIF4A1/2 impair the oxidative stress response in osteosarcoma cells to block tumor growth and metastatic capacity

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