Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment
Bcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2– overexpressing lung and breast cancer cells were more sensitive to both paclitaxel...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-01-01
|
| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S147655861380125X |
| _version_ | 1811298011069808640 |
|---|---|
| author | Amandine Savry Manon Carre Raphael Berges Amandine Rovini Isabelle Pobel Christine Chacon Diane Braguer Véronique Bourgarel-Rey |
| author_facet | Amandine Savry Manon Carre Raphael Berges Amandine Rovini Isabelle Pobel Christine Chacon Diane Braguer Véronique Bourgarel-Rey |
| author_sort | Amandine Savry |
| collection | DOAJ |
| description | Bcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2– overexpressing lung and breast cancer cells were more sensitive to both paclitaxel and vinorelbine. Bcl-2 overexpression also significantly potentiated in vivo efficacy of paclitaxel, in terms of tumor volume decrease and survival benefits, in models of nude mice bearing lung cancer xenografts. To further investigate this favorable effect of Bcl-2, a genomic approach was taken. It revealed that Bcl-2 overexpression induced up-regulation of the proapoptotic protein Bim in lung cancer cells and that, conversely, Bcl-2 silencing decreased Bim expression level. A gene regulation study implicated the transcription factor Forkhead box-containing protein, class O3a in Bim up-regulation. Lastly, we show that Bim was responsible for MTA-triggered lung cancer cell death through a dynamin-related protein 1–mediated mitochondrial fragmentation. The Bcl-2–governed Bim induction evidence offers for the first time an explanation for the favorable higher sensitivity to treatment shown by Bcl-2–overexpressing cells. We suggest that Bim could be a powerful predictive factor for tumor response to MTA chemotherapy. Our data also give new insight into some failures in the efficacy of therapies targeted against Bcl-2. |
| first_indexed | 2024-04-13T06:13:21Z |
| format | Article |
| id | doaj.art-6afa7a48fb074511bf561ba859ff26c3 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T06:13:21Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-6afa7a48fb074511bf561ba859ff26c32022-12-22T02:58:56ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022013-01-01151496010.1593/neo.121074Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer TreatmentAmandine Savry0Manon Carre1Raphael Berges2Amandine Rovini3Isabelle Pobel4Christine Chacon5Diane Braguer6Véronique Bourgarel-Rey7INSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceINSERM UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie Aix-Marseille Université, Faculté de Pharmacie Marseille Cedex FranceBcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2– overexpressing lung and breast cancer cells were more sensitive to both paclitaxel and vinorelbine. Bcl-2 overexpression also significantly potentiated in vivo efficacy of paclitaxel, in terms of tumor volume decrease and survival benefits, in models of nude mice bearing lung cancer xenografts. To further investigate this favorable effect of Bcl-2, a genomic approach was taken. It revealed that Bcl-2 overexpression induced up-regulation of the proapoptotic protein Bim in lung cancer cells and that, conversely, Bcl-2 silencing decreased Bim expression level. A gene regulation study implicated the transcription factor Forkhead box-containing protein, class O3a in Bim up-regulation. Lastly, we show that Bim was responsible for MTA-triggered lung cancer cell death through a dynamin-related protein 1–mediated mitochondrial fragmentation. The Bcl-2–governed Bim induction evidence offers for the first time an explanation for the favorable higher sensitivity to treatment shown by Bcl-2–overexpressing cells. We suggest that Bim could be a powerful predictive factor for tumor response to MTA chemotherapy. Our data also give new insight into some failures in the efficacy of therapies targeted against Bcl-2.http://www.sciencedirect.com/science/article/pii/S147655861380125X |
| spellingShingle | Amandine Savry Manon Carre Raphael Berges Amandine Rovini Isabelle Pobel Christine Chacon Diane Braguer Véronique Bourgarel-Rey Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment Neoplasia: An International Journal for Oncology Research |
| title | Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment |
| title_full | Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment |
| title_fullStr | Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment |
| title_full_unstemmed | Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment |
| title_short | Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment |
| title_sort | bcl 2 enhanced efficacy of microtubule targeting chemotherapy through bim overexpression implications for cancer treatment |
| url | http://www.sciencedirect.com/science/article/pii/S147655861380125X |
| work_keys_str_mv | AT amandinesavry bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT manoncarre bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT raphaelberges bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT amandinerovini bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT isabellepobel bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT christinechacon bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT dianebraguer bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment AT veroniquebourgarelrey bcl2enhancedefficacyofmicrotubuletargetingchemotherapythroughbimoverexpressionimplicationsforcancertreatment |