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

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 (IC 50 5 ∼7 mM, second-order rate inhibition constant of ∼810 M 21 ×min 21). 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.

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

“…Information Classification: General dephosphorylation of JAK/STAT proteins [96]. Similarly, the Protein Tyrosine Phosphatase 1B (PTP1B) formed from the PTPN1 gene promotes STAT1 and STAT3 dephosphorylation thus affecting the JAK/STAT pathway [97].…”

Long non-coding RNA TINCR promotes hepatocellular carcinoma proliferation and invasion via STAT3 signaling by direct interacting with T-cell protein tyrosine phosphatase (TCPTP)

“…The catalytic cysteine residue (cysteine 216) and its surrounding residues of TCPTP is responsible for its tyrosine phosphatase activity of TCPTP [ 20 ]. TCPTP can directly dephosphorylate STAT3 in mice models with NASH or HCC [ 19 ].…”

“…Using these methods, we successfully characterize the TINCR interacting protein, the nuclear isoform of TCPTP (T cell protein tyrosine phosphatase, TC45), which interacts with STAT3 and dephosphorylates STAT3 Y705 [ 18 ]. Furthermore, STAT3 is always activated and promotes tumor aggressiveness in human HCC [ 19 , 20 ]. Bioinformatics analyses were employed to further explore the mass spectrometry data and the cross-talk regions between TINCR and TCPTP.…”

Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play

“…The loss of TCPTP phosphatase activity may lead to excessive activation of the JAK/STAT pathway, which further changes the development of HSC. Etoposide and benzene metabolites, including etoposide quinone and benzoquinone, can irreversibly inhibit TCPTP activity, suggesting another new mechanisms for etoposide and benzene to induction of leukemia [ 115 , 116 ]. ( Fig.…”