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

Date

2009-03-26

Authors

Amine, Abdessamad
Rivera, Sofia
Opolon, Paule
Dekkal, Mehdi
Biard, Denis S. F.
Bouamar, Hakim
Louache, Fawzia
McKay, Michael J.
Bourhis, Jean
Deutsch, Eric

Journal Title

Journal ISSN

Volume Title

Publisher

Public Library of Science

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.

Description

Keywords

alphapapillomavirus, cell line, tumor, chemokine cxcl12, cytosine, humans, neoplasm metastasis, oncogene proteins, viral, organophosphonates, papillomavirus e7 proteins, receptors, cxcr4, signal transduction, rho gtp-binding proteins, rho-associated kinases

Citation

Source

PLoS ONE

Type

Journal article

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