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dc.contributor.authorCamacho, Luz-
dc.contributor.authorMeca-Cortés, Óscar-
dc.contributor.authorAbad, José Luis-
dc.contributor.authorGarcía, Simón-
dc.contributor.authorRubio, Nuria-
dc.contributor.authorCelià-Terrassa, Toni-
dc.contributor.authorCingolani, Francesca-
dc.contributor.authorBlanco, Jerónimo-
dc.contributor.authorDelgado Cirilo, Antonio-
dc.contributor.authorCasas Brugulat, Josefina-
dc.contributor.authorThomson, Timothy M.-
dc.identifierdoi: 10.1194/jlr.M032375-
dc.identifierissn: 0022-2275-
dc.identifier.citationJournal of Lipid Research 54(5): 1207-1220 (2013)-
dc.description.abstractAcid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine- 1-phosphate. AC is expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confirm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specific AC inhibitors could act by counteracting critical growth properties of these highly aggressive tumor cells. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.-
dc.description.sponsorshipThis work was supported by Ministry of Science and Innovation Grants SAF2008-00706 and SAF2011-22444 (to G.F.); Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1072 (to G.F.); Ministry of Science and Innovation Grants SAF2008-04136-C02-01 and SAF2011-24686 (to T.M.T.); Ministry of Economy and Competitivity Grant SAF2012-40017-C02-01 (to T.M.T.); Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1482 (to T.M.T.); Xarxa de Bancs de Tumours de Catalunya-Pla Director d'Oncologia and Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea “Una manera de hacer Europa” and Ministry of Economy and Competitivity Grant SAF2012-40017-C02-02 (to P.L.F.); Red Nacional de Biobancos (ReTBioH) (to P.L.F. and R.B.); Generalitat de Catalunya Grant 2009SGR1072 (to L.C.), Ministry of Science and Innovation FPU fellowship (to O.M-C.); I3P fellowship (CSIC) (to T.C-T.); and Generalitat de Catalunya FI fellowship (to F.C.)-
dc.publisherAmerican Society for Biochemistry and Molecular Biology-
dc.titleAcid ceramidase as a therapeutic target in metastatic prostate cancer-
dc.description.versionPeer Reviewed-
dc.contributor.funderGeneralitat de Catalunya-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderXarxa de Bancs de Tumors de Catalunya-
dc.contributor.funderEuropean Commission-
dc.contributor.funderRed Nacional de Biobancos (España)-
dc.contributor.funderConsejo Superior de Investigaciones Científicas (España)-
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