Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM
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...
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| Format: | Online |
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Impact Journals LLC
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741800/ |
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pubmed-4741800 |
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pubmed-47418002016-03-11 Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM Tomicic, Maja T. Meise, Ruth Aasland, Dorthe Berte, Nancy Kitzinger, Rebekka Krämer, Oliver H. Kaina, Bernd Christmann, Markus Research Paper 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. Impact Journals LLC 2015-09-16 /pmc/articles/PMC4741800/ /pubmed/26418950 Text en Copyright: © 2015 Tomicic et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Tomicic, Maja T. Meise, Ruth Aasland, Dorthe Berte, Nancy Kitzinger, Rebekka Krämer, Oliver H. Kaina, Bernd Christmann, Markus |
| spellingShingle |
Tomicic, Maja T. Meise, Ruth Aasland, Dorthe Berte, Nancy Kitzinger, Rebekka Krämer, Oliver H. Kaina, Bernd Christmann, Markus Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM |
| author_facet |
Tomicic, Maja T. Meise, Ruth Aasland, Dorthe Berte, Nancy Kitzinger, Rebekka Krämer, Oliver H. Kaina, Bernd Christmann, Markus |
| author_sort |
Tomicic, Maja T. |
| title |
Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM |
| title_short |
Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM |
| title_full |
Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM |
| title_fullStr |
Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM |
| title_full_unstemmed |
Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM |
| title_sort |
apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by jnk/c-jun-mediated induction of the bh3-only protein bim |
| description |
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. |
| publisher |
Impact Journals LLC |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741800/ |
| _version_ |
1613533930005200896 |