ß-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active ß-catenin-mediated cancer.
J Transl Med
; 21(1): 50, 2023 01 26.
Article
em En
| MEDLINE
| ID: mdl-36703130
ABSTRACT
BACKGROUND:
Although ß-catenin signaling cascade is frequently altered in human cancers, targeting this pathway has not been approved for cancer treatment.METHODS:
High-throughput screening of an FDA-approved drug library was conducted to identify therapeutics that selectively inhibited the cells with activated ß-catenin. Efficacy of iron chelator and mitochondrial inhibitor was evaluated for suppression of cell proliferation and tumorigenesis. Cellular chelatable iron levels were measured to gain insight into the potential vulnerability of ß-catenin-activated cells to iron deprivation. Extracellular flux analysis of mitochondrial function was conducted to evaluate the downstream events of iron deprivation. Chromatin immunoprecipitation, real-time quantitative PCR and immunoblotting were performed to identify ß-catenin targets. Depletion of iron-regulatory protein 2 (IRP2), a key regulator of cellular iron homeostasis, was carried out to elucidate its significance in ß-catenin-activated cells. Online databases were analyzed for correlation between ß-catenin activity and IRP2-TfR1 axis in human cancers.RESULTS:
Iron chelators were identified as selective inhibitors against ß-catenin-activated cells. Deferoxamine mesylate, an iron chelator, preferentially repressed ß-catenin-activated cell proliferation and tumor formation in mice. Mechanically, ß-catenin stimulated the transcription of IRP2 to increase labile iron level. Depletion of IRP2-sequered iron impaired ß-catenin-invigorated mitochondrial function. Moreover, mitochondrial inhibitor S-Gboxin selectively reduced ß-catenin-associated cell viability and tumor formation.CONCLUSIONS:
ß-catenin/IRP2/iron stimulation of mitochondrial energetics is targetable vulnerability of ß-catenin-potentiated cancer.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína 2 Reguladora do Ferro
/
Neoplasias
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China