Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Alkylating / pharmacology*
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Apoptosis / drug effects*
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Blotting, Western
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology*
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Dacarbazine / analogs & derivatives*
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Dacarbazine / pharmacology
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Glioma / genetics
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Glioma / metabolism
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Glioma / pathology*
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Humans
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Myeloid Cell Leukemia Sequence 1 Protein / physiology*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Temozolomide
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Tumor Cells, Cultured
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bcl-2 Homologous Antagonist-Killer Protein / physiology*
Substances
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Antineoplastic Agents, Alkylating
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BAK1 protein, human
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Small Interfering
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bcl-2 Homologous Antagonist-Killer Protein
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Dacarbazine
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Temozolomide