epi-Aszonalenin B from Aspergillus novofumigatus inhibits NF-κB activity induced by ZFTA-RELA fusion protein that drives ependymoma
| Autor: | Kazuki Ishikawa, Masaki Ishii, Takashi Yaguchi, Toshiaki Katada, Koji Ichinose, Shinya Ohata |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Molecular Structure
Oncogene Proteins Fusion Reverse Transcriptase Polymerase Chain Reaction Blotting Western NF-kappa B Transcription Factor RelA Biophysics Nuclear Proteins Neural Cell Adhesion Molecule L1 Cell Biology Intercellular Adhesion Molecule-1 Biochemistry Indole Alkaloids Gene Expression Regulation Neoplastic Aspergillus HEK293 Cells Ependymoma Doxycycline Humans Cyclin D1 Molecular Biology HeLa Cells |
| Zdroj: | Biochemical and Biophysical Research Communications. 596:104-110 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2022.01.076 |
| Popis: | Nuclear factor-kappa B (NF-κB) signaling is an intracellular signaling pathway involved in inflammatory responses and the pathogenesis of various cancers, including ependymoma, which is a rare and chemotherapy-resistant glioma. Several isoforms of fusion proteins that consist of a nuclear protein, zinc finger translocation associated (ZFTA), and RELA (ZFTA-RELA), an NF-κB-signaling effector transcription factor, cause excessive activation of the NF-κB signaling pathway and result in supratentorial ependymomas (ST-EPN-RELA). As inhibitors of NF-κB activity induced by ZFTA-RELA are expected to be therapeutic agents for ST-EPN-RELA, we established an NF-κB responsive luciferase reporter cell line that expresses the most common isoform of ZFTA-RELA in a doxycycline-dependent manner. Using this reporter cell line, we screened fungus extracts for compounds that inhibit the NF-κB activity induced by ZFTA-RELA expression and identified aszonalenin, an alkaloid from Aspergillus novofumigatus. We also purified analogs of aszonalenin, namely acetylaszonalenin and epi-aszonalenin B and C. In a luciferase assay using cells constitutively expressing luciferase (counter assay), acetylaszonalenin and epi-aszonalenin C showed non-specific inhibition of the luciferase activity. Aszonalenin and epi-aszonalenin B inhibited the NF-κB responsive luciferase activity by expressing ZFTA-RELA more strongly than the luciferase activity in the counter assay. The upregulation of endogenous NF-κB responsive genes, such as CCND1, ICAM1, and L1CAM, by ZFTA-RELA expression was inhibited by epi-aszonalenin B, but not by aszonalenin. This study suggests that epi-aszonalenin B may be a lead compound for the therapeutic development of ST-EPN-RELA. |
| Databáze: | OpenAIRE |
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