Inhibition of PlexA1-mediated brain tumor growth and tumor-associated angiogenesis using a transmembrane domain targeting peptide
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Laurent Jacob1,2,3,4, Paul Sawma5,*, Norbert Garnier6,*, Lionel A.T. Meyer1,2,3,4,*, Justine Fritz1,2,3,4,*, Thomas Hussenet1,2,3,4,*, Caroline Spenlé1,2,3,4,*, Jacky Goetz1,2,3,4,7, Julien Vermot7, Aurore Fernandez1,2,3,4, Nadège Baumlin1,2,3,4, Samia Aci-Sèche6,8, Gertraud Orend1,2,3,4, Guy Roussel1,2,3,4, Gérard Crémel1,2,3,4, Monique Genest6, Pierre Hubert5, Dominique Bagnard1,2,3,4
1MN3T Team, INSERM U1109, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3LabEx Medalis, Université de Strasbourg, Strasbourg, France
4Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
5Laboratoire d’Ingénierie des Systèmes Macromoléculaires (LISM), UMR 7255, CNRS-Aix Marseille Université, Marseille, France
6Centre de Biophysique Moléculaire, UPR 4301, CNRS, Affiliated to the University of Orléans, Orléans, France
7Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS/INSERM/UDS, Illkirch, France
8Current address: Institut de Chimie Organique et Analytique UMR, Université d'Orléans, Orléans, France
*These authors contributed equally to this work
Dominique Bagnard, email: firstname.lastname@example.org
Keywords: plexin, anti-cancer drug, angiogenesis, biomarker, glioblastoma
Received: July 11, 2016 Accepted: July 21, 2016 Published: August 05, 2016
The neuropilin-plexin receptor complex regulates tumor cell migration and proliferation and thus is an interesting therapeutic target. High expression of neuropilin-1 is indeed associated with a bad prognosis in glioma patients. Q-RTPCR and tissue-array analyses showed here that Plexin-A1 is highly expressed in glioblastoma and that the highest level of expression correlates with the worse survival of patients. We next identified a developmental and tumor-associated pro-angiogenic role of Plexin-A1. Hence, by using molecular simulations and a two-hybrid like assay in parallel with biochemical and cellular assays we developed a specific Plexin-A1 peptidic antagonist disrupting transmembrane domain-mediated oligomerization of the receptor and subsequent signaling and functional activity. We found that this peptide exhibits anti-tumor activity in vivo on different human glioblastoma models including glioma cancer stem cells. Thus, screening Plexin-A1 expression and targeting Plexin-A1 in glioblastoma patients exhibit diagnostic and therapeutic value.
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