Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling

Duval, Romain; Bui, Linh‐Chi; Mathieu, Cécile; Nian, Qing; Berthelet, Jérémy; Xu, Ximing; Haddad, Iman; Vinh, Joëlle; Dupret, Jean‐Marie; Busi, Florent; Guidez, Fabien; Chomienne, Christine; Rodrigues‐Lima, Fernando

doi:10.1074/jbc.ra119.008666

Cited by 19 publications

(7 citation statements)

References 63 publications

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“…8 D). Similarly, 5,8-dihydroxy-1,4-naphthoquinone has the same binding mode due to the oxidized reaction between the quinone and the thiol moiety of SARS-CoV-2 3CL pro , which forms the irreversible covalent adduct at the cysteine residue of the enzyme [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

Wang

et al. 2021

International Journal of Biological Macromolecules

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After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CL pro is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1018 compounds has potent inhibitory activity against SARS-CoV-2 3CL pro with the IC 50 value of 4.78 ± 1.03 μM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CL pro . Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CL pro . Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

Wang

et al. 2021

International Journal of Biological Macromolecules

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“…PTPNs, belonging to the PTP family, share the common property of possessing phosphatase activity that dephosphorylates a series of proteins, thereby governing cellular signal transduction and biological processes. Several studies have shown that PTPN2 and PTPN6 are highly expressed in hematopoietic cells and act as negative signaling regulators ( 13 , 14 ). For instance, PTPN2 dephosphorylates and inactivates signal transducer and activator of transcription (STAT) protein, which is required to maintain cellular homeostasis in the hematopoietic system ( 15 ).…”

Section: The Physiological Role Of Ptpnsmentioning

confidence: 99%

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

Tang

Qi²,

Zhou

et al. 2022

Front. Oncol.

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Since tyrosine phosphorylation is reversible and dynamic in vivo, the phosphorylation state of proteins is controlled by the opposing roles of protein tyrosine kinases (PTKs) and protein tyrosine phosphatase (PTPs), both of which perform critical roles in signal transduction. Of these, intracellular non-receptor PTPs (PTPNs), which belong to the largest class I cysteine PTP family, are essential for the regulation of a variety of biological processes, including but not limited to hematopoiesis, inflammatory response, immune system, and glucose homeostasis. Additionally, a substantial amount of PTPNs have been identified to hold crucial roles in tumorigenesis, progression, metastasis, and drug resistance, and inhibitors of PTPNs have promising applications due to striking efficacy in antitumor therapy. Hence, the aim of this review is to summarize the role played by PTPNs, including PTPN1/PTP1B, PTPN2/TC-PTP, PTPN3/PTP-H1, PTPN4/PTPMEG, PTPN6/SHP-1, PTPN9/PTPMEG2, PTPN11/SHP-2, PTPN12/PTP-PEST, PTPN13/PTPL1, PTPN14/PEZ, PTPN18/PTP-HSCF, PTPN22/LYP, and PTPN23/HD-PTP, in human cancer and immunotherapy and to comprehensively describe the molecular pathways in which they are implicated. Given the specific roles of PTPNs, identifying potential regulators of PTPNs is significant for understanding the mechanisms of antitumor therapy. Consequently, this work also provides a review on the role of non-coding RNAs (ncRNAs) in regulating PTPNs in tumorigenesis and progression, which may help us to find effective therapeutic agents for tumor therapy.

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“…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.…”

Section: Etoposide Metabolites Contribute To Therapy-related Leukemia: Non-top2 Factorsmentioning

confidence: 99%

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

Zhang

Gou

Dupret

et al. 2021

Translational Oncology

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Etoposide is a semi-synthetic glycoside derivative of podophyllotoxin, also known as VP-16. It is a widely used anticancer medicine in clinics. Unfortunately, high doses or long-term etoposide treatment can induce therapy-related leukemia. The mechanism by which etoposide induces secondary hematopoietic malignancies is still unclear. In this article, we review the potential mechanisms of etoposide induced therapy-related leukemia. Etoposide related leukemogenesis is known to depend on reactive oxidative metabolites of etoposide, notably etoposide quinone, which interacts with cellular proteins such as topoisomerases II (TOP2), CREB-binding protein (CREBBP), and T-Cell Protein Tyrosine Phosphatase (TCPTP). CYP3A4 and CYP3A5 metabolize etoposide to etoposide catechol, which readily oxidizes to etoposide quinone. As a poison of TOP2 enzymes, etoposide and its metabolites induce DNA double-stranded breaks (DSB), and the accumulation of DSB triggers cell apoptosis. If the cell survives, the DSB gives rise to the likelihood of faulty DNA repair events. The gene translocation could occur in mixed-lineage leukemia ( MLL ) gene, which is well-known in leukemogenesis. Recently, studies have revealed that etoposide metabolites, especially etoposide quinone, can covalently bind to cysteines residues of CREBBP and TCPTP enzymes, . This leads to enzyme inhibition and further affects histone acetylation and phosphorylation of the JAK-STAT pathway, thus putatively altering the proliferation and differentiation of hematopoietic stem cells (HSC). In brief, current studies suggest that etoposide and its metabolites contribute to etoposide therapy-related leukemia through TOP2 mediated DSB and impairs specific enzyme activity, such as CREBBP and TCPTP.

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Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling

Cited by 19 publications

References 63 publications

Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

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

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