Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents
Identifieur interne : 00D075 ( Main/Exploration ); précédent : 00D074; suivant : 00D076Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents
Auteurs : D. Decaudin [France] ; S. Geley [Australie] ; T. Hirsch [France] ; M. Castedo [France] ; P. Marchetti [France] ; A. Macho [France] ; R. Kofler [Australie] ; G. Kroemer [France]Source :
- Cancer research : (Baltimore) [ 0008-5472 ] ; 1997.
Descripteurs français
- Pascal (Inist)
- Etoposide, Doxorubicine, Cytarabine, Anticancéreux, Apoptose, Mort cellulaire, Cellule tumorale, Résistance, Mécanisme, Protooncogène, Mitochondrie, Potentiel membrane, Lignée cellulaire établie, Homme, In vitro, Podophyllotoxine dérivé, Anthracyclines, Pyrimidine nucléoside, Gène Bcl-2, Gène Bcl-XL.
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, I-β-D-arabinofuranosylcytosine), as well as the proapoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (Δψm) that precedes nuclear DNA fragmentation. This effect has been observed in tumor cell lines of T-lymphoid, B-lymphoid, and myelomonocytic origin in vitro. Circulating tumor cells from patients receiving chemotherapy in vivo also demonstrate a ΔΨm disruption after in vitro culture that precedes nuclear apoptosis. Transfection-enforced hyperexpression of the proto-oncogenes bcl-2 and bcl-XL protects against chemotherapy-induced apoptosis, at both the level of the mitochondrial dysfunction preceding nuclear apoptosis and the level of late nuclear apoptotic events. Bcl-2-mediated inhibition of ceramide-induced ΔΨmdisruption is observed in normal as well as anucleate cells, indicating that bcl-2 acts on an extranuclear pathway of apoptosis. In contrast to Bcl-2 and Bcl-XL, hyperexpression of the protease inhibitor cytokine response modifier A fails to protect tumor cells against chemotherapy-induced ΔΨm disruption and apoptosis, although cytokine response modifier A does prevent the ΔΨm collapse and posterior nuclear apoptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, ΔΨm disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and ΔΨm is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.
Affiliations:
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Hirsch</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Castedo, M" sort="Castedo, M" uniqKey="Castedo M" first="M." last="Castedo">M. 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Kofler</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for General and Experimental Pathology of the University of Innsbruck, Fritz-Pregl-Strasse 3</s1><s2>6020 Innsbruck</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>6020 Innsbruck</wicri:noRegion></affiliation></author><author><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G." last="Kroemer">G. Kroemer</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 Villejuif</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">97-0161198</idno><date when="1997">1997</date><idno type="stanalyst">PASCAL 97-0161198 INIST</idno><idno type="RBID">Pascal:97-0161198</idno><idno type="wicri:Area/PascalFrancis/Corpus">006A68</idno><idno type="wicri:Area/PascalFrancis/Curation">006601</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">006791</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">006791</idno><idno type="wicri:doubleKey">0008-5472:1997:Decaudin D:bcl:and:bcl</idno><idno type="wicri:Area/Main/Merge">00E227</idno><idno type="wicri:Area/Main/Curation">00D075</idno><idno type="wicri:Area/Main/Exploration">00D075</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Bcl-2 and Bcl-X<sub>L</sub> antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents</title><author><name sortKey="Decaudin, D" sort="Decaudin, D" uniqKey="Decaudin D" first="D." last="Decaudin">D. Decaudin</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Villejuif</settlement></placeName></affiliation></author><author><name sortKey="Geley, S" sort="Geley, S" uniqKey="Geley S" first="S." last="Geley">S. Geley</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for General and Experimental Pathology of the University of Innsbruck, Fritz-Pregl-Strasse 3</s1><s2>6020 Innsbruck</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>6020 Innsbruck</wicri:noRegion></affiliation></author><author><name sortKey="Hirsch, T" sort="Hirsch, T" uniqKey="Hirsch T" first="T." last="Hirsch">T. Hirsch</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Castedo, M" sort="Castedo, M" uniqKey="Castedo M" first="M." last="Castedo">M. Castedo</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Marchetti, P" sort="Marchetti, P" uniqKey="Marchetti P" first="P." last="Marchetti">P. Marchetti</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Macho, A" sort="Macho, A" uniqKey="Macho A" first="A." last="Macho">A. Macho</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Kofler, R" sort="Kofler, R" uniqKey="Kofler R" first="R." last="Kofler">R. Kofler</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute for General and Experimental Pathology of the University of Innsbruck, Fritz-Pregl-Strasse 3</s1><s2>6020 Innsbruck</s2><s3>AUS</s3><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>6020 Innsbruck</wicri:noRegion></affiliation></author><author><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G." last="Kroemer">G. Kroemer</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8</s1><s2>94801 Villejuif</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>94801 Villejuif</wicri:noRegion><wicri:noRegion>B.P. 8</wicri:noRegion><wicri:noRegion>94801 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="1997">1997</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>Anthracyclins</term><term>Antineoplastic agent</term><term>Apoptosis</term><term>Cell death</term><term>Cytarabine</term><term>Doxorubicin</term><term>Established cell line</term><term>Etoposide</term><term>Human</term><term>In vitro</term><term>Mechanism</term><term>Membrane potential</term><term>Mitochondria</term><term>Podophyllotoxine derivatives</term><term>Protooncogene</term><term>Pyrimidine nucleoside</term><term>Resistance</term><term>Tumor cell</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Etoposide</term><term>Doxorubicine</term><term>Cytarabine</term><term>Anticancéreux</term><term>Apoptose</term><term>Mort cellulaire</term><term>Cellule tumorale</term><term>Résistance</term><term>Mécanisme</term><term>Protooncogène</term><term>Mitochondrie</term><term>Potentiel membrane</term><term>Lignée cellulaire établie</term><term>Homme</term><term>In vitro</term><term>Podophyllotoxine dérivé</term><term>Anthracyclines</term><term>Pyrimidine nucléoside</term><term>Gène Bcl-2</term><term>Gène Bcl-XL</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, I-β-D-arabinofuranosylcytosine), as well as the proapoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (Δψ<sub>m</sub>) that precedes nuclear DNA fragmentation. This effect has been observed in tumor cell lines of T-lymphoid, B-lymphoid, and myelomonocytic origin in vitro. Circulating tumor cells from patients receiving chemotherapy in vivo also demonstrate a ΔΨ<sub>m</sub> disruption after in vitro culture that precedes nuclear apoptosis. Transfection-enforced hyperexpression of the proto-oncogenes bcl-2 and bcl-X<sub>L</sub> protects against chemotherapy-induced apoptosis, at both the level of the mitochondrial dysfunction preceding nuclear apoptosis and the level of late nuclear apoptotic events. Bcl-2-mediated inhibition of ceramide-induced ΔΨ<sub>m</sub>disruption is observed in normal as well as anucleate cells, indicating that bcl-2 acts on an extranuclear pathway of apoptosis. In contrast to Bcl-2 and Bcl-X<sub>L</sub>, hyperexpression of the protease inhibitor cytokine response modifier A fails to protect tumor cells against chemotherapy-induced ΔΨ<sub>m</sub> disruption and apoptosis, although cytokine response modifier A does prevent the ΔΨ<sub>m</sub> collapse and posterior nuclear apoptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, ΔΨ<sub>m</sub> disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and ΔΨ<sub>m</sub> is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Villejuif</li></settlement></list><tree><country name="France"><region name="Île-de-France"><name sortKey="Decaudin, D" sort="Decaudin, D" uniqKey="Decaudin D" first="D." last="Decaudin">D. Decaudin</name></region><name sortKey="Castedo, M" sort="Castedo, M" uniqKey="Castedo M" first="M." last="Castedo">M. Castedo</name><name sortKey="Hirsch, T" sort="Hirsch, T" uniqKey="Hirsch T" first="T." last="Hirsch">T. Hirsch</name><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G." last="Kroemer">G. Kroemer</name><name sortKey="Macho, A" sort="Macho, A" uniqKey="Macho A" first="A." last="Macho">A. Macho</name><name sortKey="Marchetti, P" sort="Marchetti, P" uniqKey="Marchetti P" first="P." last="Marchetti">P. Marchetti</name></country><country name="Australie"><noRegion><name sortKey="Geley, S" sort="Geley, S" uniqKey="Geley S" first="S." last="Geley">S. Geley</name></noRegion><name sortKey="Kofler, R" sort="Kofler, R" uniqKey="Kofler R" first="R." last="Kofler">R. Kofler</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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