title: Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM.
abstract: The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs.
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Tomicic
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Meise
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Aasland
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Berte
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Kitzinger
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.affiliation: Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Christmann
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D020552:Comet Assay; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D015376:Nimustine / Q000494:pharmacology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D000077204:Temozolomide; D015854:Up-Regulation
chemical_list: D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D015376:Nimustine; D003606:Dacarbazine; D048670:MAP Kinase Kinase 4; D000077204:Temozolomide
keywords: ACNU; BIM; JNK; TMZ; high-grade gliomas