Bak and Mcl-1 are essential for Temozolomide induced cell death in human glioma
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Catherine Gratas1,2,3, Quentin Séry1,2,4, Marion Rabé1,2, Lisa Oliver1,2,3 and François M. Vallette1,2,4
1. Centre de Recherche en Cancérologie Nantes Angers, UMR INSERM 892 / CNRS 6299
2. Université de Nantes, Nantes F-44000, France
3. CHU de Nantes, Nantes F-44805, France.
4. Institut de Cancérologie de l’Ouest-Centre René Gauducheau, St Herblain F-44805, France
François M. Vallette, email:
Keywords: temozolomide, glioma, apoptosis , Bcl-2 family
Received: November 29, 2013 Accepted: January 1, 2014 Published: January 1, 2014
Temozolomide (TMZ) is an alkylating agent used for the treatment of glioblastoma multiforme (GBM), the main form of human brain tumours in adults. It has been reported that TMZ induced DNA lesions that subsequently trigger cell death but the actual mechanisms involved in the process are still unclear. We investigated the implication of major proteins of the Bcl-2 family in TMZ-induced cell death in GBM cell lines at concentrations closed to that reached in the brain during the treatments. We did not observe modulation of autophagy at these concentrations but we found an induction of apoptosis. Using RNA interference, we showed that TMZ induced apoptosis is dependent on the pro-apoptotic protein Bak but independent of the pro-apoptotic protein Bax. Apoptosis was not enhanced by ABT-737, an inhibitor of Bcl-2/Bcl-Xl/Bcl-W but not Mcl-1. The knock-down of Mcl-1 expression increased TMZ induced apoptosis. Our results identify a Mcl-1/Bak axis for TMZ induced apoptosis in GBM and thus unravel a target to overcome therapeutic resistance toward TMZ.
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