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.
Varin
Emilie
E
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.
Denoyelle
Christophe
C
Brotin
Emilie
E
Meryet-Figuière
Matthieu
M
Giffard
Florence
F
Abeilard
Edwige
E
Goux
Didier
D
Gauduchon
Pascal
P
Icard
Philippe
P
Poulain
Laurent
L
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