title: Auranofin is a potent suppressor of osteosarcoma metastasis.
abstract: Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10-20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long-term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29-42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Eleni
authors.initials: E
authors.lastname: Topkas
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cumming
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Mehlika
authors.initials: M
authors.lastname: Hazar-Rethinam
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Orla Margaret
authors.initials: OM
authors.lastname: Gannon
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Melinda
authors.initials: M
authors.lastname: Burgess
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Nicholas Andrew
authors.initials: NA
authors.lastname: Saunders
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Liliana
authors.initials: L
authors.lastname: Endo-Munoz
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D018501:Antirheumatic Agents; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D001310:Auranofin; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2
keywords: auranofin; metastasis; osteosarcoma; oxidative stress; thioredoxin reductase