Blocking Hypoxia-Induced Autophagy in Tumors Restores Cytotoxic T-Cell Activity and Promotes Regression
Identifieur interne : 001600 ( Main/Exploration ); précédent : 001599; suivant : 001601Blocking Hypoxia-Induced Autophagy in Tumors Restores Cytotoxic T-Cell Activity and Promotes Regression
Auteurs : MUHAMMAD ZAEEM NOMAN [France] ; Bassam Janji [Luxembourg (pays)] ; Bozena Kaminska [Pologne] ; Kris Van Moer [Luxembourg (pays)] ; Sandrine Pierson [Luxembourg (pays)] ; Piotr Przanowski [Pologne] ; Stéphanie Buart [France] ; Guy Berchem [Luxembourg (pays)] ; Pedro Romero [Suisse] ; Fathia Mami-Chouaib [France] ; Salem Chouaib [France]Source :
- Cancer research : (Baltimore) [ 0008-5472 ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Oxygène.
English descriptors
- KwdEn :
Abstract
The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.
Affiliations:
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Zaeem Noman" last="Muhammad Zaeem Noman">MUHAMMAD ZAEEM NOMAN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Unité INSERM U753, Institut de Cancérologie Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut de Cancérologie Gustave Roussy</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Janji, Bassam" sort="Janji, Bassam" uniqKey="Janji B" first="Bassam" last="Janji">Bassam Janji</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé)</s1><s2>Luxembourg City</s2><s3>LUX</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Luxembourg (pays)</country><wicri:noRegion>Luxembourg City</wicri:noRegion></affiliation></author><author><name sortKey="Kaminska, Bozena" sort="Kaminska, Bozena" uniqKey="Kaminska B" first="Bozena" last="Kaminska">Bozena Kaminska</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute</s1><s2>Warsaw</s2><s3>POL</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Pologne</country><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Moer, Kris Van" sort="Moer, Kris Van" uniqKey="Moer K" first="Kris Van" last="Moer">Kris Van Moer</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé)</s1><s2>Luxembourg City</s2><s3>LUX</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Luxembourg (pays)</country><wicri:noRegion>Luxembourg City</wicri:noRegion></affiliation></author><author><name sortKey="Pierson, Sandrine" sort="Pierson, Sandrine" uniqKey="Pierson S" first="Sandrine" last="Pierson">Sandrine Pierson</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé)</s1><s2>Luxembourg City</s2><s3>LUX</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Luxembourg (pays)</country><wicri:noRegion>Luxembourg City</wicri:noRegion></affiliation></author><author><name sortKey="Przanowski, Piotr" sort="Przanowski, Piotr" uniqKey="Przanowski P" first="Piotr" last="Przanowski">Piotr Przanowski</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute</s1><s2>Warsaw</s2><s3>POL</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Pologne</country><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Buart, Stephanie" sort="Buart, Stephanie" uniqKey="Buart S" first="Stéphanie" last="Buart">Stéphanie Buart</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Unité INSERM U753, Institut de Cancérologie Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut de Cancérologie Gustave Roussy</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Berchem, Guy" sort="Berchem, Guy" uniqKey="Berchem G" first="Guy" last="Berchem">Guy Berchem</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé)</s1><s2>Luxembourg City</s2><s3>LUX</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Luxembourg (pays)</country><wicri:noRegion>Luxembourg City</wicri:noRegion></affiliation></author><author><name sortKey="Romero, Pedro" sort="Romero, Pedro" uniqKey="Romero P" first="Pedro" last="Romero">Pedro Romero</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Translational Tumor Immunology group, Ludwig Center for Cancer Research, University of Lausanne</s1><s2>Lausanne</s2><s3>CHE</s3><sZ>9 aut.</sZ></inist:fA14><country>Suisse</country><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Mami Chouaib, Fathia" sort="Mami Chouaib, Fathia" uniqKey="Mami Chouaib F" first="Fathia" last="Mami-Chouaib">Fathia Mami-Chouaib</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Unité INSERM U753, Institut de Cancérologie Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut de Cancérologie Gustave Roussy</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Chouaib, Salem" sort="Chouaib, Salem" uniqKey="Chouaib S" first="Salem" last="Chouaib">Salem Chouaib</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Unité INSERM U753, Institut de Cancérologie Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Institut de Cancérologie Gustave Roussy</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Cancer research : (Baltimore)</title><title level="j" type="abbreviated">Cancer res. : (Baltimore)</title><idno type="ISSN">0008-5472</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Cancer research : (Baltimore)</title><title level="j" type="abbreviated">Cancer res. : (Baltimore)</title><idno type="ISSN">0008-5472</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autophagy</term><term>Biological activity</term><term>Cytotoxic T lymphocyte</term><term>Hypoxia</term><term>Malignant tumor</term><term>Oxygen</term><term>Regression</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Hypoxie</term><term>Autophagie</term><term>Tumeur maligne</term><term>Lymphocyte T cytotoxique</term><term>Activité biologique</term><term>Régression</term><term>Oxygène</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Oxygène</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.</div></front></TEI><affiliations><list><country><li>France</li><li>Luxembourg (pays)</li><li>Pologne</li><li>Suisse</li></country><region><li>Canton de Vaud</li></region><settlement><li>Lausanne</li></settlement></list><tree><country name="France"><noRegion><name sortKey="Muhammad Zaeem Noman" sort="Muhammad Zaeem Noman" uniqKey="Muhammad Zaeem Noman" last="Muhammad Zaeem Noman">MUHAMMAD ZAEEM NOMAN</name></noRegion><name sortKey="Buart, Stephanie" sort="Buart, Stephanie" uniqKey="Buart S" first="Stéphanie" last="Buart">Stéphanie Buart</name><name sortKey="Chouaib, Salem" sort="Chouaib, Salem" uniqKey="Chouaib S" first="Salem" last="Chouaib">Salem Chouaib</name><name sortKey="Mami Chouaib, Fathia" sort="Mami Chouaib, Fathia" uniqKey="Mami Chouaib F" first="Fathia" last="Mami-Chouaib">Fathia Mami-Chouaib</name></country><country name="Luxembourg (pays)"><noRegion><name sortKey="Janji, Bassam" sort="Janji, Bassam" uniqKey="Janji B" first="Bassam" last="Janji">Bassam Janji</name></noRegion><name sortKey="Berchem, Guy" sort="Berchem, Guy" uniqKey="Berchem G" first="Guy" last="Berchem">Guy Berchem</name><name sortKey="Moer, Kris Van" sort="Moer, Kris Van" uniqKey="Moer K" first="Kris Van" last="Moer">Kris Van Moer</name><name sortKey="Pierson, Sandrine" sort="Pierson, Sandrine" uniqKey="Pierson S" first="Sandrine" last="Pierson">Sandrine Pierson</name></country><country name="Pologne"><noRegion><name sortKey="Kaminska, Bozena" sort="Kaminska, Bozena" uniqKey="Kaminska B" first="Bozena" last="Kaminska">Bozena Kaminska</name></noRegion><name sortKey="Przanowski, Piotr" sort="Przanowski, Piotr" uniqKey="Przanowski P" first="Piotr" last="Przanowski">Piotr Przanowski</name></country><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Romero, Pedro" sort="Romero, Pedro" uniqKey="Romero P" first="Pedro" last="Romero">Pedro Romero</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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