Cisplatin causes covalent inhibition of protein-tyrosine phosphatase 1B (PTP1B) through reaction with its active site cysteine: Molecular, cellular and in vivo mice studies - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Biomedicine and Pharmacotherapy Année : 2022

Cisplatin causes covalent inhibition of protein-tyrosine phosphatase 1B (PTP1B) through reaction with its active site cysteine: Molecular, cellular and in vivo mice studies

Résumé

Protein tyrosine phosphatase 1B (PTP1B) is a critical regulator of different signalling cascades such as the EGFR pathway. The biological importance of PTP1B is further evidenced by knockout mice studies and the identification of recurrent mutations/deletions in PTP1B linked to metabolic and oncogenic alterations. Cisplatin is among the most widely used anticancer drug. The biological effects of cisplatin are thought to arise primarily from DNA damaging events involving cisplatin-DNA adducts. However, increasing evidence indicate that the biological properties of cisplatin could also rely on the perturbation of other processes such as cell signalling through direct interaction with certain cysteine residues in proteins. Here, we provide molecular, cellular and in vivo evidence suggesting that PTP1B is a target of cisplatin. Mechanistic studies indicate that cisplatin inhibited PTP1B in an irreversible manner and binds covalently to the catalytic cysteine residue of the enzyme. Accordingly, experiments conducted in cells and mice exposed to cisplatin showed inhibition of endogenous PTP1B and concomitant increase in tyrosine phosphorylation of EGFR. These findings are consistent with previous studies showing tyrosine phosphorylation-dependent activation of the EGFR pathway by cisplatin and with recent studies suggesting PTP1B inhibition by cisplatin and other platinum complexes. Importantly, our work provides novel mechanistic evidence that PTP1B is a protein target of cisplatin and is inhibited by this drug at molecular, cellular and in vivo levels. In addition, our work may contribute to the understanding of the pathways undergoing modulation upon cisplatin administration beyond of the established genotoxic effect of cisplatin.
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hal-04281628 , version 1 (13-11-2023)

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Rongxing Liu, Wenchao Zhang, Panhong Gou, Jérémy Berthelet, Qing Nian, et al.. Cisplatin causes covalent inhibition of protein-tyrosine phosphatase 1B (PTP1B) through reaction with its active site cysteine: Molecular, cellular and in vivo mice studies. Biomedicine and Pharmacotherapy, 2022, 153, pp.113372. ⟨10.1016/j.biopha.2022.113372⟩. ⟨hal-04281628⟩
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