PT  - JOURNAL ARTICLE
AU  - Nian, Qing
AU  - Berthelet, Jérémy
AU  - Zhang, Wenchao
AU  - Bui, Linh-Chi
AU  - Liu, Rongxing
AU  - Xu, Ximing
AU  - Duval, Romain
AU  - Ganesan, Saravanan
AU  - Leger, Thibaut
AU  - Chomienne, Christine
AU  - Busi, Florent
AU  - Guidez, Fabien
AU  - Dupret, Jean-Marie
AU  - Rodrigues Lima, Fernando
TI  - T-Cell Protein Tyrosine Phosphatase Is Irreversibly Inhibited by Etoposide-Quinone, a Reactive Metabolite of the Chemotherapy Drug Etoposide
AID  - 10.1124/mol.119.116319
DP  - 2019 Aug 01
TA  - Molecular Pharmacology
PG  - 297--306
VI  - 96
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/96/2/297.short
4100  - http://molpharm.aspetjournals.org/content/96/2/297.full
SO  - Mol Pharmacol2019 Aug 01; 96
AB  - 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 = ∼7 μM, second-order rate inhibition constant of ∼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.