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A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities.
Namjoo, Mohadeseh; Ghafouri, Hossein; Assareh, Elham; Aref, Amir Reza; Mostafavi, Ebrahim; Hamrahi Mohsen, Ali; Balalaie, Saeed; Broussy, Sylvain; Asghari, S Mohsen.
Afiliación
  • Namjoo M; Department of Biology, University Campus II, University of Guilan, Rasht P.O. Box 14155-6619, Iran.
  • Ghafouri H; Department of Biology, Faculty of Sciences, University of Guilan, Rasht P.O. Box 14155-6619, Iran.
  • Assareh E; Department of Biology, Faculty of Sciences, University of Guilan, Rasht P.O. Box 14155-6619, Iran.
  • Aref AR; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Mostafavi E; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Hamrahi Mohsen A; Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran P.O. Box 1841, Iran.
  • Balalaie S; Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran P.O. Box 1841, Iran.
  • Broussy S; CiTCoM, UMR CNRS 8038, U1268 INSERM, UFR de Pharmacie, Faculté de Santé, Université Paris Cité, 75006 Paris, France.
  • Asghari SM; Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran P.O. Box 1841, Iran.
Pharmaceuticals (Basel) ; 16(6)2023 Jun 20.
Article en En | MEDLINE | ID: mdl-37375853
ABSTRACT
Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear structures of VGB3 (named C-VGB3 and L-VGB3, respectively) using receptor binding and cell proliferation assays, molecular docking, and evaluation of antiangiogenic and antitumor activities in the 4T1 mouse mammary carcinoma tumor (MCT) model showed that loop formation is essential for peptide functionality. C-VGB3 inhibited proliferation and tubulogenesis of human umbilical vein endothelial cells (HUVECs), accounting for the abrogation of VEGFR2, p-VEGFR2 and, subsequently, PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. In 4T1 MCT cells, C-VGB3 inhibited cell proliferation, VEGFR2 expression and phosphorylation, the PI3K/AKT/mTOR pathway, FAK/Paxillin, and the epithelial-to-mesenchymal transition cascade. The apoptotic effects of C-VGB3 on HUVE and 4T1 MCT cells were inferred from annexin-PI and TUNEL staining and activation of P53, caspase-3, caspase-7, and PARP1, which mechanistically occurred through the intrinsic pathway mediated by Bcl2 family members, cytochrome c, Apaf-1 and caspase-9, and extrinsic pathway via death receptors and caspase-8. These data indicate that binding regions shared by VEGF family members may be important in developing novel pan-VEGFR inhibitors that are highly relevant in the pathogenesis of angiogenesis-related diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Pharmaceuticals (Basel) Año: 2023 Tipo del documento: Article País de afiliación: Irán

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Pharmaceuticals (Basel) Año: 2023 Tipo del documento: Article País de afiliación: Irán
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