T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide.
Fiche publication
Date publication
août 2019
Journal
Molecular pharmacology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Nian Q, Berthelet J, Zhang W, Bui LC, Liu R, Xu X, Duval R, Ganesan S, Leger T, Chomienne C, Busi F, Guidez F, Dupret JM, Rodrigues Lima F
Lien Pubmed
Résumé
Etoposide is a widely prescribed anticancer drug that is, however, associated with an increased risk of secondary leukemia. Although the molecular basis underlying the development of these leukemias remains poorly understood, increasing evidence implicates the interaction of etoposide metabolites [i.e., etoposide quinone (EQ)] with topoisomerase II enzymes. However, effects of etoposide quinone on other cellular targets could also be at play. We investigated whether T-cell protein tyrosine phosphatase (TCPTP), a protein tyrosine phosphatase that plays a key role in normal and malignant hematopoiesis through regulation of Janus kinase/signal transducer and activator of transcription signaling, could be a target of EQ. We report here that EQ is an irreversible inhibitor of TCPTP phosphatase (IC = ∼7 M, second-order rate inhibition constant of ∼810 M⋅min). No inhibition was observed with the parent drug. The inhibition by EQ was found to be due to the formation of a covalent adduct at the catalytic cysteine residue in the active site of TCPTP. Exposure of human hematopoietic cells (HL60 and Jurkat) to EQ led to inhibition of endogenous TCPTP and concomitant increase in STAT1 tyrosine phosphorylation. Our results suggest that in addition to alteration of topoisomerase II functions, EQ could also contribute to etoposide-dependent leukemogenesis through impairment of key hematopoietic signaling enzymes, such as TCPTP.
Mots clés
Binding Sites, Catalytic Domain, Cysteine, metabolism, Down-Regulation, Etoposide, chemistry, Gene Expression Regulation, drug effects, HL-60 Cells, Humans, Jurkat Cells, Phosphorylation, drug effects, Protein Tyrosine Phosphatase, Non-Receptor Type 2, chemistry, Quinones, chemistry, STAT1 Transcription Factor, metabolism
Référence
Mol Pharmacol. 2019 08;96(2):297-306