The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity

Peng Hsu Chen, Wan Lin Shen, Chwen-Ming Shih, Kuo Hao Ho, Chia-Hsiung Cheng, Cheng-Wei Lin, Chin-Cheng Lee, Ann Jeng Liu, Ku-Chung Chen

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) is the high-grade primary glioma in adults. Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug for clinical therapy. However, the expense of TMZ therapy and increasing drug resistance to TMZ decreases its therapeutic effects. Therefore, our aim was to investigate the detailed molecular mechanisms of TMZ-mediated cytotoxicity to enhance the efficacy of TMZ in clinical GBM therapy. First, TMZ-mediated gene expression profiles and networks in U87-MG cells were identified by transcriptome microarray and bioinformatic analyses. Cation transport regulator-like protein 1 (CHAC1) was the most highly TMZ-upregulated gene. Overexpression and knockdown of CHAC1 expression significantly influenced TMZ-mediated cell viability, apoptosis, caspase-3 activation, and poly(ADP ribose) polymerase (PARP) degradation. The c-Jun N-terminal kinase (JNK)1/c-JUN pathway was identified to participate in TMZ-upregulated CHAC1 expression via transcriptional control. Furthermore, CHAC1 levels were significantly decreased in GBM cell lines, TCGA array data, and tumor tissues. Overexpression of CHAC1 enhanced glioma apoptotic death via caspase-3/9 activation, PARP degradation, autophagy formation, reactive oxygen species generation, increased intracellular calcium, and loss of the mitochondria membrane potential. Finally, we also identified that TMZ significantly reduced Notch3 levels, which are upregulated in gliomas. TMZ also induced CHAC1 to bind to the Notch3 protein and inhibit Notch3 activation, resulting in attenuation of Notch3-mediated downstream signaling pathways. These results emphasize that CHAC1-inhibited Notch3 signaling can influence TMZ-mediated cytotoxicity. Our findings may provide novel therapeutic strategies for future glioblastoma therapy.

Original languageEnglish
Pages (from-to)300-314
Number of pages15
JournalNeuropharmacology
Volume116
DOIs
Publication statusPublished - Apr 1 2017

Fingerprint

temozolomide
Glioma
Glioblastoma
Poly(ADP-ribose) Polymerases
Transcriptome
Caspase 3
Mitogen-Activated Protein Kinase 8

Keywords

  • CHAC1
  • Glioblastoma multiforme
  • JNK1/c-JUN pathway
  • Notch3
  • Temozolomide (TMZ)

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. / Chen, Peng Hsu; Shen, Wan Lin; Shih, Chwen-Ming; Ho, Kuo Hao; Cheng, Chia-Hsiung; Lin, Cheng-Wei; Lee, Chin-Cheng; Liu, Ann Jeng; Chen, Ku-Chung.

In: Neuropharmacology, Vol. 116, 01.04.2017, p. 300-314.

Research output: Contribution to journalArticle

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abstract = "Glioblastoma multiforme (GBM) is the high-grade primary glioma in adults. Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug for clinical therapy. However, the expense of TMZ therapy and increasing drug resistance to TMZ decreases its therapeutic effects. Therefore, our aim was to investigate the detailed molecular mechanisms of TMZ-mediated cytotoxicity to enhance the efficacy of TMZ in clinical GBM therapy. First, TMZ-mediated gene expression profiles and networks in U87-MG cells were identified by transcriptome microarray and bioinformatic analyses. Cation transport regulator-like protein 1 (CHAC1) was the most highly TMZ-upregulated gene. Overexpression and knockdown of CHAC1 expression significantly influenced TMZ-mediated cell viability, apoptosis, caspase-3 activation, and poly(ADP ribose) polymerase (PARP) degradation. The c-Jun N-terminal kinase (JNK)1/c-JUN pathway was identified to participate in TMZ-upregulated CHAC1 expression via transcriptional control. Furthermore, CHAC1 levels were significantly decreased in GBM cell lines, TCGA array data, and tumor tissues. Overexpression of CHAC1 enhanced glioma apoptotic death via caspase-3/9 activation, PARP degradation, autophagy formation, reactive oxygen species generation, increased intracellular calcium, and loss of the mitochondria membrane potential. Finally, we also identified that TMZ significantly reduced Notch3 levels, which are upregulated in gliomas. TMZ also induced CHAC1 to bind to the Notch3 protein and inhibit Notch3 activation, resulting in attenuation of Notch3-mediated downstream signaling pathways. These results emphasize that CHAC1-inhibited Notch3 signaling can influence TMZ-mediated cytotoxicity. Our findings may provide novel therapeutic strategies for future glioblastoma therapy.",
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AU - Lee, Chin-Cheng

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