epi-Aszonalenin B from Aspergillus novofumigatus inhibits NF-κB activity induced by ZFTA-RELA fusion protein that drives ependymoma.
Aspergillus
/ chemistry
Blotting, Western
Cyclin D1
/ genetics
Doxycycline
/ pharmacology
Ependymoma
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
HEK293 Cells
HeLa Cells
Humans
Indole Alkaloids
/ chemistry
Intercellular Adhesion Molecule-1
Molecular Structure
NF-kappa B
/ antagonists & inhibitors
Neural Cell Adhesion Molecule L1
/ genetics
Nuclear Proteins
/ genetics
Oncogene Proteins, Fusion
/ genetics
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factor RelA
/ genetics
Ependymoma
Fungi
Inhibitor screening
NF-κB
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
12 03 2022
12 03 2022
Historique:
received:
17
01
2022
accepted:
19
01
2022
pubmed:
9
2
2022
medline:
16
3
2022
entrez:
8
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35131506
pii: S0006-291X(22)00096-1
doi: 10.1016/j.bbrc.2022.01.076
pii:
doi:
Substances chimiques
ICAM1 protein, human
0
Indole Alkaloids
0
NF-kappa B
0
Neural Cell Adhesion Molecule L1
0
Nuclear Proteins
0
Oncogene Proteins, Fusion
0
RELA protein, human
0
Transcription Factor RelA
0
aszonalenin
0V5DQ674AU
Intercellular Adhesion Molecule-1
126547-89-5
Cyclin D1
136601-57-5
Doxycycline
N12000U13O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104-110Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no competing interests.