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Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor.
Miller, Anna V; Hicks, Mark A; Nakajima, Wataru; Richardson, Amanda C; Windle, Jolene J; Harada, Hisashi.
Afiliação
  • Miller AV; Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
PLoS One ; 8(4): e60685, 2013.
Article em En | MEDLINE | ID: mdl-23577147
Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim(-/-) MEFs (mouse embryonic fibroblasts), the bim(-/-) mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak (-/-) MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax(-/-) MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Proteínas Proto-Oncogênicas / Paclitaxel / Apoptose / Proteínas Reguladoras de Apoptose / Proteína X Associada a bcl-2 / Proteína Killer-Antagonista Homóloga a bcl-2 / Proteínas de Membrana / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: PLoS One Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Proteínas Proto-Oncogênicas / Paclitaxel / Apoptose / Proteínas Reguladoras de Apoptose / Proteína X Associada a bcl-2 / Proteína Killer-Antagonista Homóloga a bcl-2 / Proteínas de Membrana / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: PLoS One Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos