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Acriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditions

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dc.contributor.authorMartí Díaz, Román
dc.contributor.authorCabezas Herrera, Juan
dc.contributor.authorGoding, Colin
dc.contributor.authorMontenegro Arce, María Fernanda
dc.contributor.authorRodríguez López, José Neptuno
dc.contributor.authorSánchez del Campo Ferrer, Luis
dc.contributor.departmentBioquímica y Biología Molecular Aes
dc.date.accessioned2024-02-01T11:35:20Z
dc.date.available2024-02-01T11:35:20Z
dc.date.issued2020-12-31
dc.description©2020. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in Cancers. To access the final edited and published work see https://doi.org/10.3390/cancers13010102es
dc.description.abstractHypoxia-inducible factor (HIF)-1α is constitutively expressed in melanoma cells under normoxic conditions and its elevated expression correlates with the aggressiveness of melanoma tumors. Here, we used acriflavine, a potent inhibitor of HIF-1α dimerization, as a tool to investigate whether HIF-1α-regulated pathways contribute to the growth of melanoma cells under normoxia. We observed that acriflavine differentially modulated HIF-1α-regulated targets in melanoma under normoxic conditions, although acriflavine treatment resulted in over-expression of vascular endothelial growth factor (VEGF), its action clearly downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1), a well-known target of HIF-1α. Consequently, downregulation of PDK1 by acrifavine resulted in reduced glucose availability and suppression of the Warburg effect in melanoma cells. In addition, by inhibiting the AKT and RSK2 phosphorylation, acriflavine also avoided protective pathways necessary for survival under conditions of oxidative stress. Interestingly, we show that acriflavine targets activating transcription factor 4 (ATF4) for proteasomal degradation while suppressing the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and a melanoma oncogene. Since acriflavine treatment results in the consistent death of melanoma cells, our results suggest that inhibition of HIF-1α function in melanoma could open new avenues for the treatment of this deadly disease regardless of the hypoxic condition of the tumor.es
dc.formatapplication/pdfes
dc.format.extent17es
dc.identifier.citationCancers. Volumen: 13 ,nº: 1, 2020
dc.identifier.doi10.3390/cancers13010102
dc.identifier.issn2072-6694
dc.identifier.urihttp://hdl.handle.net/10201/138353
dc.languageenges
dc.publisherMDPIes
dc.relationÁmbito del proyecto: Nacional y regional - Agencia financiadora: Ministerio de Economía y Competitividad (MINECO; Co-financing with Fondos FEDER) y Fundación Séneca, the Región de Murcia (FS-RM) - Código o número del acuerdo de subvención: SAF2016-77241-R, 20809/PI/18 y RYC-2016-20036es
dc.relation.isreplacedby10.3390/cancers13010102es
dc.relation.publisherversionhttps://doi.org/10.3390/cancers13010102es
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAcriflavinees
dc.subjectMITFes
dc.subjectHIF-1es
dc.subjectATF4es
dc.subjectGlucose metabolismes
dc.subjectMelanoma
dc.subjectOxygen homeostasis
dc.subject.otherCDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísicaes
dc.titleAcriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditionses
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
relation.isAuthorOfPublication2d4e44e6-9dda-4146-8aef-fe0c6b5a8b8f
relation.isAuthorOfPublication36d7ac7e-b9a7-477c-8f7e-f03d4cc834c1
relation.isAuthorOfPublicationf702e5be-3f82-4512-b2a2-6c69a5cb98ff
relation.isAuthorOfPublication.latestForDiscovery2d4e44e6-9dda-4146-8aef-fe0c6b5a8b8f
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