Novel anti-metastatic action of Cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV+ tumor cells

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dc.contributor.authorAmine, Abdessamad
dc.contributor.authorRivera, Sofia
dc.contributor.authorOpolon, Paule
dc.contributor.authorDekkal, Mehdi
dc.contributor.authorBiard, Denis S. F.
dc.contributor.authorBouamar, Hakim
dc.contributor.authorLouache, Fawzia
dc.contributor.authorMcKay, Michael J.
dc.contributor.authorBourhis, Jean
dc.contributor.authorDeutsch, Eric
dc.contributor.authorVozenin-Brotons, Marie-Catherine
dc.date.accessioned2015-10-25T23:53:26Z
dc.date.available2015-10-25T23:53:26Z
dc.date.issued2009-03-26
dc.date.updated2015-12-09T07:48:48Z
dc.description.abstractCervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1alpha and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1alpha/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1alpha stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (in vitro and in vivo) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1alpha/CXCR4 to the metastatic process. E6 and E7 silencing using stable knock-down and the approved anti-viral agent, Cidofovir decreased CXCR4 gene expression as well as both, constitutive and SDF-1alpha-induced cell invasion. In addition, Cidofovir inhibited lung metastasis (both adhesion and invasion) supporting contribution of E6 and E7 oncoproteins to the metastatic process. Finally, potential signals activated downstream SDF-1alpha/CXCR4 and involved in lung homing of E6/E7-expressing tumor cells were investigated. The contribution of the Rho/ROCK pathway was suggested by the inhibitory effect triggered by Cidofovir and further confirmed using Y-27632 (a small molecule ROCK inhibitor). These data suggest a novel and highly translatable therapeutic approach to cervix cancer, by inhibition of adhesion and invasion of circulating HPV-positive tumor cells, using Cidofovir and/or ROCK inhibition.
dc.description.sponsorshipA. A. and S. R. are fellows of the Association pour la Recherche sur le Cancer. D. B. acknowledges a grant from Electricite de France. This study was partly supported by the Association pour la Recherche sur le Cancer, contract nu 3881 and 4970.en_AU
dc.format14 pages
dc.identifier.issn1932-6203en_AU
dc.identifier.urihttp://hdl.handle.net/1885/16073
dc.publisherPublic Library of Science
dc.rights© 2009 Amine et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.sourcePLoS ONE
dc.subjectalphapapillomavirus
dc.subjectcell line, tumor
dc.subjectchemokine cxcl12
dc.subjectcytosine
dc.subjecthumans
dc.subjectneoplasm metastasis
dc.subjectoncogene proteins, viral
dc.subjectorganophosphonates
dc.subjectpapillomavirus e7 proteins
dc.subjectreceptors, cxcr4
dc.subjectsignal transduction
dc.subjectrho gtp-binding proteins
dc.subjectrho-associated kinases
dc.titleNovel anti-metastatic action of Cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV+ tumor cells
dc.typeJournal article
dcterms.dateAccepted2009-02-16
local.bibliographicCitation.issue3en_AU
local.bibliographicCitation.startpagee5018en_AU
local.contributor.affiliationAmine, Abdessamad, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationRivera, Sofia, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationOpolon, Paule, Institut Gustave Roussy , Franceen_AU
local.contributor.affiliationDekkal, Mehdi, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationBiard, Denis, Institut Andre Lwoff, Franceen_AU
local.contributor.affiliationBouamar, Hakim, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationLouache, Fawzia, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationMcKay, Michael, College of Medicine, Biology and Environment, CMBE ANU Medical School, ANU Medical School, The Australian National Universityen_AU
local.contributor.affiliationBourhis, Jean, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationDeutsch, Eric, Institut Gustave Roussy, Franceen_AU
local.contributor.affiliationVozenin-Broton, Marie-Catherine, Institut Gustave Roussy, Franceen_AU
local.contributor.authoruida276689en_AU
local.description.notesImported from ARIESen_AU
local.identifier.absfor119999en_AU
local.identifier.ariespublicationu4201517xPUB186en_AU
local.identifier.citationvolume4en_AU
local.identifier.doi10.1371/journal.pone.0005018en_AU
local.identifier.essn1932-6203en_AU
local.identifier.scopusID2-s2.0-63449122542
local.identifier.uidSubmittedByu3488905en_AU
local.publisher.urlhttps://www.plos.org/en_AU
local.type.statusPublished Versionen_AU

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