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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Cadherins / genetics
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Cadherins / metabolism
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics*
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Dogs
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Endothelial Cells / metabolism
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Epithelial-Mesenchymal Transition / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Human Umbilical Vein Endothelial Cells
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Humans
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MCF-7 Cells
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Melanoma, Experimental / genetics*
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Melanoma, Experimental / pathology
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Mice
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Neoplasm Invasiveness / genetics
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Neoplasm Metastasis
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / genetics*
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Vimentin* / genetics
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Vimentin* / metabolism
Substances
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Antigens, CD
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Cadherins
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Poly(ADP-ribose) Polymerase Inhibitors
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Vimentin
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cadherin 5
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
Grants and funding
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 manuscript.