title: Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells.
abstract: Cervical 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.
authors.affiliation: Laboratoire UPRES EA 27-10 Radiosensibilité des Tumeurs et Tissus Sains, Institut Gustave Roussy/Institut de Radioprotection et de Sureté Nucléaire, Villejuif, France.
authors.forename: Abdessamad
authors.initials: A
authors.lastname: Amine
authors.forename: Sofia
authors.initials: S
authors.lastname: Rivera
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Mehdi
authors.initials: M
authors.lastname: Dekkal
authors.forename: Denis S F
authors.initials: DS
authors.lastname: Biard
authors.forename: Hakim
authors.initials: H
authors.lastname: Bouamar
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McKay
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin-Brotons