Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells
Identifieur interne : 001383 ( Pmc/Curation ); précédent : 001382; suivant : 001384Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells
Auteurs : Abdessamad Amine [France] ; Sofia Rivera [France] ; Paule Opolon [France] ; Mehdi Dekkal [France] ; Denis S. F. Biard [France] ; Hakim Bouamar [France] ; Fawzia Louache [France] ; Michael J. Mckay [Australie] ; Jean Bourhis [France] ; Eric Deutsch [France] ; Marie-Catherine Vozenin-Brotons [France]Source :
- PLoS ONE [ 1932-6203 ] ; 2009.
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-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α 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 (
Url:
DOI: 10.1371/journal.pone.0005018
PubMed: 19325708
PubMed Central: 2657827
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Tumor Cells</title>
<author><name sortKey="Amine, Abdessamad" sort="Amine, Abdessamad" uniqKey="Amine A" first="Abdessamad" last="Amine">Abdessamad Amine</name>
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<author><name sortKey="Biard, Denis S F" sort="Biard, Denis S F" uniqKey="Biard D" first="Denis S. F." last="Biard">Denis S. F. Biard</name>
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<author><name sortKey="Bouamar, Hakim" sort="Bouamar, Hakim" uniqKey="Bouamar H" first="Hakim" last="Bouamar">Hakim Bouamar</name>
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<author><name sortKey="Louache, Fawzia" sort="Louache, Fawzia" uniqKey="Louache F" first="Fawzia" last="Louache">Fawzia Louache</name>
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<author><name sortKey="Mckay, Michael J" sort="Mckay, Michael J" uniqKey="Mckay M" first="Michael J." last="Mckay">Michael J. Mckay</name>
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<author><name sortKey="Bourhis, Jean" sort="Bourhis, Jean" uniqKey="Bourhis J" first="Jean" last="Bourhis">Jean Bourhis</name>
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<author><name sortKey="Deutsch, Eric" sort="Deutsch, Eric" uniqKey="Deutsch E" first="Eric" last="Deutsch">Eric Deutsch</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Laboratoire UPRES EA 27-10 Radiosensibilité des tumeurs et tissus sains, Institut Gustave Roussy/Institut de Radioprotection et de Sureté Nucléaire, Villejuif, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
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<author><name sortKey="Vozenin Brotons, Marie Catherine" sort="Vozenin Brotons, Marie Catherine" uniqKey="Vozenin Brotons M" first="Marie-Catherine" last="Vozenin-Brotons">Marie-Catherine Vozenin-Brotons</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Laboratoire UPRES EA 27-10 Radiosensibilité des tumeurs et tissus sains, Institut Gustave Roussy/Institut de Radioprotection et de Sureté Nucléaire, Villejuif, France</addr-line>
</nlm:aff>
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<front><div type="abstract" xml:lang="en"><p>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-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α 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 (<italic>in vitro</italic>
and <italic>in vivo</italic>
) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/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-1α-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-1α/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.</p>
</div>
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<title-group><article-title>Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV<sup>+</sup>
Tumor Cells</article-title>
<alt-title alt-title-type="running-head">Anti-Metastatic Action of CDF</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Amine</surname>
<given-names>Abdessamad</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rivera</surname>
<given-names>Sofia</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Opolon</surname>
<given-names>Paule</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dekkal</surname>
<given-names>Mehdi</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Biard</surname>
<given-names>Denis S. F.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bouamar</surname>
<given-names>Hakim</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Louache</surname>
<given-names>Fawzia</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McKay</surname>
<given-names>Michael J.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bourhis</surname>
<given-names>Jean</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deutsch</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vozenin-Brotons</surname>
<given-names>Marie-Catherine</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Laboratoire UPRES EA 27-10 Radiosensibilité des tumeurs et tissus sains, Institut Gustave Roussy/Institut de Radioprotection et de Sureté Nucléaire, Villejuif, France</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>UMR 8121 Laboratoire de vectorologie et transfert de gènes, Institut Gustave Roussy, Villejuif, France</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>CEA-DSV-iRCM / INSERM U935. Institut A. Lwoff-CNRS, BP 8, Villejuif, France</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>INSERM U 790, Institut Gustave Roussy, Villejuif, France</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Australian National University and The Canberra Hospital, Canberra, Australia</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Hotchin</surname>
<given-names>Neil</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">University of Birmingham, United Kingdom</aff>
<author-notes><corresp id="cor1">* E-mail: <email>vozenin@igr.fr</email>
</corresp>
<fn fn-type="con"><p>Conceived and designed the experiments: AA SR MD HB MJM ED MCVB. Performed the experiments: AA SR MD DSFB HB MCVB. Analyzed the data: AA SR PO MD DSFB MJM ED MCVB. Contributed reagents/materials/analysis tools: AA SR PO DSFB HB FL MJM JB ED MCVB. Wrote the paper: PO DSFB MJM JB ED MCVB.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2009</year>
</pub-date>
<pub-date pub-type="epub"><day>26</day>
<month>3</month>
<year>2009</year>
</pub-date>
<volume>4</volume>
<issue>3</issue>
<elocation-id>e5018</elocation-id>
<history><date date-type="received"><day>19</day>
<month>10</month>
<year>2008</year>
</date>
<date date-type="accepted"><day>16</day>
<month>2</month>
<year>2009</year>
</date>
</history>
<copyright-statement>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.</copyright-statement>
<copyright-year>2009</copyright-year>
<abstract><p>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-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α 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 (<italic>in vitro</italic>
and <italic>in vivo</italic>
) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/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-1α-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-1α/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.</p>
</abstract>
<counts><page-count count="14"></page-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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