T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide - Archive ouverte HAL Access content directly
Journal Articles Molecular Pharmacology Year : 2019

T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide

(1) , (1) , (1) , (1) , (1) , (2) , (3) , (4) , (5) , (4, 6) , (1) , (4) , (1) , (1)
1
2
3
4
5
6
Romain Duval

Abstract

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 (IC50 = similar to 7 mu M, second-order rate inhibition constant of similar to 810 M-1.min(-1)). 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.
Fichier principal
Vignette du fichier
mol.119.116319.pdf (1.17 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-03201556 , version 1 (15-11-2022)

Identifiers

Cite

Qing Nian, Jeremy Berthelet, Wenchao Zhang, Linh-Chi Bui, Rongxing Liu, et al.. T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide. Molecular Pharmacology, 2019, 96 (2), pp.297-306. ⟨10.1124/mol.119.116319⟩. ⟨hal-03201556⟩
16 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More