Downregulation of Bcl-xL and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy.
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.
Unité BioTICLA (Biologie et Thérapies Innovantes des Cancers Localement Agressifs) du Groupe Régional d'Etudes sur le Cancer (EA 1772, Université de Caen Basse-Normandie et IFR146 ICORE), Centre de Lutte Contre le Cancer François Baclesse, Avenue du Général Harris, BP5026, 14076 Caen Cedex 05, France.
Emilie
E
Varin
Christophe
C
Denoyelle
Emilie
E
Brotin
Matthieu
M
Meryet-Figuière
Florence
F
Giffard
Edwige
E
Abeilard
Didier
D
Goux
Pascal
P
Gauduchon
Philippe
P
Icard
Laurent
L
Poulain
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D046529:Microscopy, Electron, Transmission; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D002945:Cisplatin