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http://hdl.handle.net/2445/208394
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DC Field | Value | Language |
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dc.contributor.author | Tonelotto, Valentina | - |
dc.contributor.author | Costa Garcia, Marcel | - |
dc.contributor.author | O’Reilly, Eve | - |
dc.contributor.author | Smith, Kaelin Francis | - |
dc.contributor.author | Slater, Kayleigh | - |
dc.contributor.author | Dillon, Eugene T. | - |
dc.contributor.author | Pendino, Marzia | - |
dc.contributor.author | Higgins, Catherine | - |
dc.contributor.author | Sist, Paola | - |
dc.contributor.author | Bosch, Rosa | - |
dc.contributor.author | Passamonti, Sabina | - |
dc.contributor.author | Piulats, Josep M. | - |
dc.contributor.author | Villanueva, Alberto | - |
dc.contributor.author | Tramer, Federica | - |
dc.contributor.author | Vanella, Luca | - |
dc.contributor.author | Carey, Michelle | - |
dc.contributor.author | Kennedy, Breandán N. | - |
dc.date.accessioned | 2024-03-05T12:35:56Z | - |
dc.date.available | 2024-03-05T12:35:56Z | - |
dc.date.issued | 2024-02-10 | - |
dc.identifier.issn | 2058-7716 | - |
dc.identifier.uri | http://hdl.handle.net/2445/208394 | - |
dc.description.abstract | Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM. | - |
dc.format.extent | 18 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Springer Science and Business Media LLC | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1038/s41420-023-01773-8 | - |
dc.relation.ispartof | Cell Death Discovery, 2024, vol. 10, num. 1 | - |
dc.relation.uri | https://doi.org/10.1038/s41420-023-01773-8 | - |
dc.rights | cc by (c) Tonelotto, Valentina et al., 2024 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Úvea | - |
dc.subject.classification | Càncer | - |
dc.subject.other | Uvea | - |
dc.subject.other | Cancer | - |
dc.title | 1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2024-02-26T12:35:04Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 38341410 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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s41420-023-01773-8.pdf | 6.67 MB | Adobe PDF | View/Open |
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