Journal Article

Downregulation of Bcl-x<sub>L</sub> and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy

Emilie Varin, Christophe Denoyelle, Emilie Brotin, Matthieu Meryet-Figuière, Florence Giffard, Edwige Abeilard, Didier Goux, Pascal Gauduchon, Philippe Icard and Laurent Poulain

in Carcinogenesis

Volume 31, issue 6, pages 984-993
Published in print June 2010 | ISSN: 0143-3334
Published online February 2010 | e-ISSN: 1460-2180 | DOI:
Downregulation of Bcl-xL and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy

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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-xL in MPM chemoresistance. Since it has been recently suggested that Mcl-1 cooperates with Bcl-xL for protection against cell death, we investigated the response of mesothelioma cell lines to the downregulation of Bcl-xL (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-xL 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-xL downregulation. Strikingly, we observed that the simultaneous inhibition of Bcl-xL 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-xL and Mcl-1, alone or in combination with conventional chemotherapy, for the treatment of MPM.

Journal Article.  6593 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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