title: Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition.
abstract: BACKGROUND
  Glioblastoma multiforme is the most common glioma in adults and carries a poor prognosis, due to tumor recurrence despite aggressive treatment. Such relapse has been attributed to the persistence of glioma stemlike cells (GSCs), a subpopulation of glioma cells with stem cell properties. Thus, targeting these cells will be critical to achieving meaningful improvement in glioblastoma multiforme survival. We investigated the role of β1-integrin signaling as one such potential target.
  
  
  METHODS
  We used GSCs isolated from primary human gliomas and maintained in stem cell conditions. We manipulated β1-integrin signaling using a self-assembling peptide amphiphile (PA) displaying the IKVAV (isoleucine-lysine-valine-alanine-valine) epitope as well as lentiviral overexpression, and we assayed the effects on downstream effectors and apoptosis using immunofluorescence.
  
  
  RESULTS
  We show that β1-integrin expression correlates with decreased survival in glioma patients and that β1-integrin is highly expressed by GSCs. The IKVAV PA potently increases immobilized β1-integrin at the GSC membrane, activating integrin-linked kinase while inhibiting focal adhesion kinase (FAK). The IKVAV PA induces striking apoptosis in GSCs via this FAK inhibition, which is enhanced in combination with inhibition of epidermal growth factor receptor (EGFR). Conversely, lentiviral overexpression of β1-integrin renders GSCs resistant to EGFR inhibition, which was overcome by FAK inhibition.
  
  
  CONCLUSIONS
  These observations reveal a role for β1-integrin signaling through FAK in GSC treatment resistance and introduce self-assembling PAs as a novel new therapeutic approach for overcoming this resistance.
authors: Department of Neurology, Northwestern University, Chicago, Illinois, USA. maya@fsm.northwestern.edu
authors: Maya
authors: M
authors: Srikanth
authors: Sunit
authors: S
authors: Das
authors: Eric J
authors: EJ
authors: Berns
authors: Juno
authors: J
authors: Kim
authors: Samuel I
authors: SI
authors: Stupp
authors: John A
authors: JA
authors: Kessler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D057139:Nanofibers; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D019012:Integrin beta1; D007797:Laminin; D010446:Peptide Fragments; D012333:RNA, Messenger; C083321:isoleucyl-lysyl-valyl-alanyl-valine; C512478:EGFR protein, human; D066246:ErbB Receptors; D051416:Focal Adhesion Protein-Tyrosine Kinases