Arsenic activated GLUT1-mTORC1/HIF-1α-PKM2 positive feedback networks promote proliferation and migration of bladder epithelial cells.
Sci Total Environ
; 947: 174538, 2024 Oct 15.
Article
de En
| MEDLINE
| ID: mdl-38977090
ABSTRACT
Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Arsenic
/
Mouvement cellulaire
/
Prolifération cellulaire
/
Cellules épithéliales
/
Transporteur de glucose de type 1
/
Sous-unité alpha du facteur-1 induit par l'hypoxie
/
Complexe-1 cible mécanistique de la rapamycine
Limites:
Animals
/
Humans
Langue:
En
Journal:
Sci Total Environ
/
Sci. total environ
/
Science of the total environment
Année:
2024
Type de document:
Article
Pays de publication:
Pays-Bas