Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c-Met to up-regulate angiogenesis and lung adenocarcinoma growth.

Autor: Kastana P; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece., Ntenekou D; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece., Mourkogianni E; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece., Enake MK; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece., Xanthopoulos A; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece., Choleva E; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece., Marazioti A; Laboratory of Molecular Respiratory Carcinogenesis, Faculty of Medicine, Department of Physiology, University of Patras, Patras, Greece., Nikou S; Department of Anatomy, Faculty of Medicine, University of Patras, Patras, Greece., Akwii RG; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA., Papadaki E; Department of Anatomy, Faculty of Medicine, University of Patras, Patras, Greece., Gramage E; Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain., Herradón G; Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain., Stathopoulos GT; Laboratory of Molecular Respiratory Carcinogenesis, Faculty of Medicine, Department of Physiology, University of Patras, Patras, Greece., Mikelis CM; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece.; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA., Papadimitriou E; Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2023 Sep 01; Vol. 153 (5), pp. 1051-1066. Date of Electronic Publication: 2023 Jun 01.
DOI: 10.1002/ijc.34564
Abstrakt: Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A 165 (VEGFA 165 ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1 -/- and Ptprz1 +/+ mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1 -/- lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1 +/+ LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1 -/- compared with Ptprz1 +/+ mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (β 3 ) integrin is decreased in Ptprz1 -/- LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1 -/- mice. A selective PTPRZ1 TP inhibitor, VEGFA 165 and PTN also activate c-Met and Akt in a PTPRZ1-dependent manner in endothelial cells, and their stimulatory effects are abolished by the c-Met TK inhibitor (TKI) crizotinib. Altogether, our data suggest that low PTPRZ1 expression is linked to worse LUAD prognosis and response to c-Met TKIs and uncover for the first time the role of PTPRZ1 in mediating c-Met activation by VEGFA and PTN.
(© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
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