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

  • Int J Cancer. 2023 Sep 1;153(5):1051-1066. doi: 10.1002/ijc.34564.
Pinelopi Kastana  1 ,  Despoina Ntenekou  1 ,  Eleni Mourkogianni  1 ,  Michaela-Karina Enake  1 ,  Athanasios Xanthopoulos  1 ,  Effrosyni Choleva  1 ,  Antonia Marazioti  2 ,  Sophia Nikou  3 ,  Racheal G Akwii  4 ,  Eleni Papadaki  3 ,  Esther Gramage  5 ,  Gonzalo Herradón  5 ,  Georgios T Stathopoulos  2 ,  Constantinos M Mikelis  1  4 ,  Evangelia Papadimitriou  1
Affiliations
  • 1. Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece.
  • 2. Laboratory of Molecular Respiratory Carcinogenesis, Faculty of Medicine, Department of Physiology, University of Patras, Patras, Greece.
  • 3. Department of Anatomy, Faculty of Medicine, University of Patras, Patras, Greece.
  • 4. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
  • 5. Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain.
PMID: 37260355 DOI: 10.1002/ijc.34564
Abstract

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 A165 (VEGFA165 ) 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 (β3 ) 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, VEGFA165 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.

Keywords
VEGFA; endothelial cells; hepatocyte growth factor receptor; integrin; pleiotrophin.
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