Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment

Autor: Amandine Savry, Manon Carre, Raphael Berges, Amandine Rovini, Isabelle Pobel, Christine Chacon, Diane Braguer, Véronique Bourgarel-Rey
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: Neoplasia: An International Journal for Oncology Research, Vol 15, Iss 1, Pp 49-60 (2013)
Druh dokumentu: article
ISSN: 1476-5586
1522-8002
DOI: 10.1593/neo.121074
Popis: 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.
Databáze: Directory of Open Access Journals
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