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Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin.
Kegelman, Timothy P; Wu, Bainan; Das, Swadesh K; Talukdar, Sarmistha; Beckta, Jason M; Hu, Bin; Emdad, Luni; Valerie, Kristoffer; Sarkar, Devanand; Furnari, Frank B; Cavenee, Webster K; Wei, Jun; Purves, Angela; De, Surya K; Pellecchia, Maurizio; Fisher, Paul B.
Afiliação
  • Kegelman TP; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • Wu B; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
  • Das SK; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • Talukdar S; VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Beckta JM; VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Hu B; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • Emdad L; Department of Radiation Oncology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Valerie K; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • Sarkar D; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • Furnari FB; VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Cavenee WK; VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Wei J; VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Purves A; Department of Radiation Oncology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • De SK; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University (VCU), Richmond, VA 23298.
  • Pellecchia M; VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
  • Fisher PB; VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
Proc Natl Acad Sci U S A ; 114(2): 370-375, 2017 01 10.
Article em En | MEDLINE | ID: mdl-28011764
ABSTRACT
Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Glioblastoma / Sinteninas / Invasividade Neoplásica Limite: Animals / Female / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Glioblastoma / Sinteninas / Invasividade Neoplásica Limite: Animals / Female / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2017 Tipo de documento: Article