Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells.
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-adhe...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2657827?pdf=render |
| _version_ | 1828526259913621504 |
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| author | Abdessamad Amine Sofia Rivera Paule Opolon Mehdi Dekkal Denis S F Biard Hakim Bouamar Fawzia Louache Michael J McKay Jean Bourhis Eric Deutsch Marie-Catherine Vozenin-Brotons |
| author_facet | Abdessamad Amine Sofia Rivera Paule Opolon Mehdi Dekkal Denis S F Biard Hakim Bouamar Fawzia Louache Michael J McKay Jean Bourhis Eric Deutsch Marie-Catherine Vozenin-Brotons |
| author_sort | Abdessamad Amine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T21:21:27Z |
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| id | doaj.art-5a932c835e5d43869d6b3e8006e93894 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T21:21:27Z |
| publishDate | 2009-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-5a932c835e5d43869d6b3e8006e938942022-12-22T00:50:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0143e501810.1371/journal.pone.0005018Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells.Abdessamad AmineSofia RiveraPaule OpolonMehdi DekkalDenis S F BiardHakim BouamarFawzia LouacheMichael J McKayJean BourhisEric DeutschMarie-Catherine Vozenin-BrotonsCervical 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.http://europepmc.org/articles/PMC2657827?pdf=render |
| spellingShingle | Abdessamad Amine Sofia Rivera Paule Opolon Mehdi Dekkal Denis S F Biard Hakim Bouamar Fawzia Louache Michael J McKay Jean Bourhis Eric Deutsch Marie-Catherine Vozenin-Brotons Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells. PLoS ONE |
| title | Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells. |
| title_full | Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells. |
| title_fullStr | Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells. |
| title_full_unstemmed | Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells. |
| title_short | Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells. |
| title_sort | novel anti metastatic action of cidofovir mediated by inhibition of e6 e7 cxcr4 and rho rock signaling in hpv tumor cells |
| url | http://europepmc.org/articles/PMC2657827?pdf=render |
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