Rodríguez, María IsabelPeralta-Leal, AndreínaO'Valle, FranciscoRodriguez-Vargas, José ManuelGonzalez-Flores, AriannysMajuelos-Melguizo, JaraLópez, LauraSerrano, SantiagoGarcía de Herreros, AntonioRodríguez-Manzaneque, Juan CarlosFernández, RubénMoral, Raimundo G DelAlmodóvar, José Mariano deOliver, F Javier2014-06-232014-06-232013-06-13Rodríguez 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 Genet.. 2013 ; 9(6):e10035311553-7390http://hdl.handle.net/10668/1640Journal Article; Research Support, Non-U.S. Gov't;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.enAntígenos CDNeoplasias de la MamaCadherinasLínea Celular TumoralTransformación Celular NeoplásicaPerrosCélulas EndotelialesTransición Epitelial-MesenquimalFemeninoRegulación Neoplásica de la Expresión GénicaCélulas Endoteliales de la Vena Umbilical HumanaHumanosCélulas MCF-7RatonesMelanoma ExperimentalInvasividad NeoplásicaMetástasis de la NeoplasiaPoli(ADP-Ribosa) PolimerasasVimentinaMedical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Antigens, Differentiation::Antigens, CDMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Breast NeoplasmsMedical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Cell Adhesion Molecules::CadherinsMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, TumorMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Cell Transformation, NeoplasticMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Carnivora::Canidae::DogsMedical Subject Headings::Anatomy::Cells::Epithelial Cells::Endothelial CellsMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Transdifferentiation::Epithelial-Mesenchymal TransitionMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, NeoplasticMedical Subject Headings::Anatomy::Cells::Epithelial Cells::Endothelial Cells::Human Umbilical Vein Endothelial CellsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Diseases::Neoplasms::Neoplasms, Experimental::Melanoma, ExperimentalMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm InvasivenessMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm MetastasisMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Glycosyltransferases::Pentosyltransferases::ADP Ribose Transferases::Poly(ADP-ribose) PolymerasesMedical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Polymers::Biopolymers::Intermediate Filament Proteins::VimentinMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::MCF-7 Cellsresearch article23785295open access10.1371/journal.pgen.10035311553-7404PMC3681683