Research Papers:

Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM

Maja T. Tomicic, Ruth Meise, Dorthe Aasland, Nancy Berte, Rebekka Kitzinger, Oliver H. Krämer, Bernd Kaina _ and Markus Christmann

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Oncotarget. 2015; 6:33755-33768. https://doi.org/10.18632/oncotarget.5274

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Maja T. Tomicic1,*, Ruth Meise1,*, Dorthe Aasland1, Nancy Berte1, Rebekka Kitzinger1, Oliver H. Krämer1, Bernd Kaina1, Markus Christmann1

1Department of Toxicology, University Medical Center Mainz, D-55131 Mainz, Germany

*These authors have contributed equally to this work

Correspondence to:

Markus Christmann, e-mail: [email protected]

Maja T. Tomicic, e-mail: [email protected]

Keywords: TMZ, ACNU, high-grade gliomas, BIM, JNK

Abbreviations: AP-1, activator protein 1; JNK, c-Jun N-terminal kinase; DSB, DNA double-strand breaks; ACNU, nimustine, (1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride; TMZ, temozolomide

Received: April 30, 2015     Accepted: September 03, 2015     Published: September 16, 2015


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.

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