Downregulation of Bcl-xL and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy.
Carcinogenesis
; 31(6): 984-93, 2010 Jun.
Article
em En
| MEDLINE
| ID: mdl-20142415
ABSTRACT
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited response to platinum-based chemotherapy. Several lines of evidence support a role for the anti-apoptotic protein Bcl-x(L) in MPM chemoresistance. Since it has been recently suggested that Mcl-1 cooperates with Bcl-x(L) for protection against cell death, we investigated the response of mesothelioma cell lines to the downregulation of Bcl-x(L) (alone or in combination with cisplatin) and the potential interest of its concomitant inhibition with that of Mcl-1. Using RNA interference, we showed that Bcl-x(L) depletion sensitized two highly chemoresistant mesothelioma cell lines to cisplatin and that under this treatment, one cell line, MSTO-211H, displayed an apoptotic type of cell death, whereas the other, NCI-H28, evidenced mainly necrotic-type cell death. Otherwise, the inhibition of Mcl-1 by cisplatin may contribute to this induction of cell death observed after Bcl-x(L) downregulation. Strikingly, we observed that the simultaneous inhibition of Bcl-x(L) and Mcl-1 using small interfering RNA (siRNA) induced a massive cell death in the absence of chemotherapy and was sufficient to avoid escape to treatment in MSTO-211H cells. In NCI-H28, the addition of a low cisplatin concentration allowed to impede the long-term recovery observed after treatment by the siRNA combination. Together, these findings provide a strong molecular basis for the clinical evaluation of therapies targeting both Bcl-x(L) and Mcl-1, alone or in combination with conventional chemotherapy, for the treatment of MPM.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação para Baixo
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Cisplatino
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Apoptose
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Proteínas Proto-Oncogênicas c-bcl-2
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Proteína bcl-X
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Mesotelioma
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Carcinogenesis
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
França