PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation

Rodríguez, María Isabel; Peralta-Leal, Andreína; O'Valle, Francisco; Rodríguez-Vargas, José Manuel; González-Flores, Ariannys; Majuelos-Melguizo, Jara; López Muñoz, Laura; Serrano, Santiago; García de Herreros, Antonio; Rodríguez-Manzaneque, Juan Carlos; Fernández Montes, Rubén D.; del Moral, Raimundo G.; de Almodovar, José Mariano; Oliver, F. Javier

PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation

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dc.contributor.author Rodríguez, María Isabelca
dc.contributor.author Peralta-Leal, Andreínaca
dc.contributor.author O'Valle, Franciscoca
dc.contributor.author Rodríguez-Vargas, José Manuelca
dc.contributor.author González-Flores, Ariannysca
dc.contributor.author Majuelos-Melguizo, Jaraca
dc.contributor.author López Muñoz, Lauraca
dc.contributor.author Serrano, Santiagoca
dc.contributor.author García de Herreros, Antonioca
dc.contributor.author Rodríguez-Manzaneque, Juan Carlosca
dc.contributor.author Fernández Montes, Rubén D.ca
dc.contributor.author del Moral, Raimundo G.ca
dc.contributor.author de Almodovar, José Marianoca
dc.contributor.author Oliver, F. Javierca
dc.date.accessioned 2015-04-29T07:24:01Z
dc.date.available 2015-04-29T07:24:01Z
dc.date.issued 2013ca
dc.description.abstract PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.en
dc.description.sponsorship This work was supported by Ministerio de Ciencia e Innovación SAF2006-01094, SAF2009-13281-C02-01, Fundación La Caixa BM06-219-0 and Junta de Andalucía P07-CTS-0239 and CTS-6602 to FJO, Ministerio de Educación y Ciencia SAF2007-64597; CICYT: SAF2009-13281-C02-02; Junta de Andalucía, P06-CTS-01385 to JMRdA and grants CEIC (P10-CTS5865) and FEDER-ISCIII (PI10/00883) to JCR-M. AGdH has been funded by grants from ‘‘Fundación Científica de la Asociación Española Contra el Cáncer’’, Ministerio de Ciencia y Tecnología SAF2010-16089, and ‘‘Fundación La Marató de TV3’’. JCR-M has been funded by Grants CEIC (P1=-CTS5865) and FEDER-ISCIII (PI10/00883). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscripten
dc.description.sponsorship Baulida and García de Herreros' labs is supported by the Instituto de Salud Carlos III (PI12/ 00257 and D012/0036/0005, part of the Plan Nacional I+D+ I and cofounded by the ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional-FEDER), the Fundación Científica Asociación Española Contra el Cáncer (Ayudas a grupos estables de investigación, 2010-1) and the Ministerio de Economía y Competitividad (SAF2013-4889-C2-1R).
dc.format.mimetype application/pdfca
dc.identifier.citation Rodriguez MI, Peralta-Leal A, O'Valle F, Rodriguez-Vargas JM, Gonzalez-Flores A, Majuelos-Melguizo J et al. PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation. PLoS Genetics. 2013;9(6):e1003531. DOI: 10.1371/journal.pgen.1003531ca
dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1003531
dc.identifier.issn 1553-7390ca
dc.identifier.uri http://hdl.handle.net/10230/23484
dc.language.iso engca
dc.publisher Public Library of Science (PLoS)ca
dc.relation.ispartof PLoS Genetics. 2013;9(6):e1003531
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-4889
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-13281
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2007-64597
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2006-01094
dc.rights © Rodriguez MI, Peralta-Leal A, O'Valle F, Rodriguez-Vargas JM, Gonzalez-Flores A, Majuelos-Melguizo J et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution...(CC BY) (http://creativecommons.org/licenses/by/2.5/).ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/2.5/
dc.subject.other Melanomaca
dc.subject.other Mama -- Càncer -- Aspectes genèticsca
dc.title PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformationen
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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