Fenofibrate inhibits hypoxia-inducible factor-1 alpha and carbonic anhydrase expression through activation of AMP-activated protein kinase/HO-1/Sirt1 pathway in glioblastoma cells.
HIF-1α
HO-1
SIRT1
fenofibrate
glioblastoma
Journal
Environmental toxicology
ISSN: 1522-7278
Titre abrégé: Environ Toxicol
Pays: United States
ID NLM: 100885357
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
revised:
27
08
2021
received:
08
03
2021
accepted:
29
08
2021
pubmed:
15
9
2021
medline:
5
11
2021
entrez:
14
9
2021
Statut:
ppublish
Résumé
Cancer and its associated conditions have significant impacts on public health at many levels worldwide, and cancer is the leading cause of death among adults. Peroxisome proliferator-activated receptor α (PPARα)-specific agonists, fibrates, have been approved by the Food and Drug Administration for managing hyperlipidemia. PPARα-specific agonists exert anti-cancer effects in many human cancer types, including glioblastoma (GBM). Recently, we have reported that the hypoxic state in GBM stabilizes hypoxia-inducible factor-1 alpha (HIF-1α), thus contributing to tumor escape from immune surveillance by activating the expression of the pH-regulating protein carbonic anhydrase IX (CA9). In this study, we aimed to study the regulatory effects of the PPARα agonist fibrate on the regulation of HIF-1α expression and its downstream target protein in GBM. Our findings showed that fenofibrate is the high potency compound among the various fibrates that inhibit hypoxia-induced HIF-1α and CA9 expression in GBM. Moreover, fenofibrate-inhibited HIF-1α expression is mediated by HO-1 activation in GBM cells through the AMP-activated protein kinase (AMPK) pathway. In addition, fenofibrate-enhanced HO-1 upregulation activates SIRT1 and leads to subsequent accumulation of SIRT1 in the nucleus, which further promotes HIF-1α deacetylation and inhibits CA9 expression. Using a protein synthesis inhibitor, cycloheximide, we also observed that fenofibrate inhibited HIF-1α protein synthesis. In addition, the administration of the proteasome inhibitor MG132 showed that fenofibrate promoted HIF-1α protein degradation in GBM. Hence, our results indicate that fenofibrate is a useful anti-GBM agent that modulates hypoxia-induced HIF-1α expression through multiple cellular pathways.
Substances chimiques
Hypoxia-Inducible Factor 1, alpha Subunit
0
AMP-Activated Protein Kinases
EC 2.7.11.31
SIRT1 protein, human
EC 3.5.1.-
Sirtuin 1
EC 3.5.1.-
Carbonic Anhydrases
EC 4.2.1.1
Fenofibrate
U202363UOS
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2551-2561Subventions
Organisme : China Medical University, Taiwan
Organisme : Ministry of Science and Technology
Organisme : Taichung Tzu Chi Hospital
Informations de copyright
© 2021 Wiley Periodicals LLC.
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