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
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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.
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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
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PLoS ONE
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Journal article
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