PFKFB3 works on the FAK-STAT3-SOX2 axis to regulate the stemness in MPM.
Br J Cancer
; 127(7): 1352-1364, 2022 10.
Article
em En
| MEDLINE
| ID: mdl-35794237
ABSTRACT
BACKGROUND:
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm and often acquires chemoresistance by increasing stemness in tumour tissue, thereby generating cancer stem cells (CSCs). CSCs escape treatment by deploying metabolic pathways to trigger dormancy or proliferation, also gaining the ability to exit and re-enter the cell cycle to hide their cellular identity.METHODS:
We employed various cellular and biochemical assays to identify the role of the glycolytic enzyme PFKFB3, by knocking it down and pharmacologically inhibiting it with PFK158, to determine its anticancer effects in vitro and in vivo by targeting the CSC population in MPM.RESULTS:
Here, we have identified PFKFB3 as a strategic player to target the CSC population in MPM and demonstrated that both pharmacologic (PFK158) and genetic inhibition of PFKFB3 destroy the FAK-Stat3-SOX2 nexus resulting in a decline in conspicuous stem cell markers viz. ALDH, CD133, CD44, SOX2. Inhibition of PFKFB3 accumulates p21 and p27 in the nucleus by decreasing SKP2. Lastly, PFK158 diminishes tumour-initiating cells (TICs) mediated MPM xenograft in vivo.CONCLUSIONS:
This study confers a comprehensive and mechanistic function of PFKFB3 in CSC maintenance that may foster exceptional opportunities for targeted small molecule blockade of the TICs in MPM.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Mesotelioma Maligno
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Br J Cancer
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos