title: PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation.
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.
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain. mirlara@ipb.csic.es
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez
authors.forename: Andreína
authors.initials: A
authors.lastname: Peralta-Leal
authors.forename: Francisco
authors.initials: F
authors.lastname: O'Valle
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Rodriguez-Vargas
authors.forename: Ariannys
authors.initials: A
authors.lastname: Gonzalez-Flores
authors.forename: Jara
authors.initials: J
authors.lastname: Majuelos-Melguizo
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.forename: Santiago
authors.initials: S
authors.lastname: Serrano
authors.forename: Antonio García
authors.initials: AG
authors.lastname: de Herreros
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Rodríguez-Manzaneque
authors.forename: Rubén
authors.initials: R
authors.lastname: Fernández
authors.forename: Raimundo G
authors.initials: RG
authors.lastname: Del Moral
authors.forename: José Mariano
authors.initials: JM
authors.lastname: de Almodóvar
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Oliver
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004285:Dogs; D042783:Endothelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D014746:Vimentin; D000099152:Cadherin 5; C499320:PARP1 protein, human