1. Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition
- Author
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John A. Kessler, Eric J. Berns, Maya Srikanth, Samuel I. Stupp, Sunit Das, and Juno Kim
- Subjects
Cancer Research ,Blotting, Western ,Nanofibers ,Fluorescent Antibody Technique ,Apoptosis ,Mice, SCID ,Biology ,Real-Time Polymerase Chain Reaction ,Immunoenzyme Techniques ,Focal adhesion ,Mice ,Cell Movement ,Mice, Inbred NOD ,Glioma ,Cell Adhesion ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Immunoprecipitation ,RNA, Messenger ,Epidermal growth factor receptor ,Cell adhesion ,In Situ Hybridization, Fluorescence ,Cell Proliferation ,Brain Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Kinase ,Cell growth ,Integrin beta1 ,Flow Cytometry ,medicine.disease ,Peptide Fragments ,ErbB Receptors ,Oncology ,Focal Adhesion Protein-Tyrosine Kinases ,Basic and Translational Investigations ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,Laminin ,Neurology (clinical) ,Stem cell - 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 b1-integrin signaling as one such potential target. Methods. We used GSCs isolated from primary human gliomas and maintained in stem cell conditions. We manipulated b1-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 b1-integrin expression correlates with decreased survival in glioma patients and that b1integrin is highly expressed by GSCs. The IKVAV PA potently increases immobilized b1-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 b1-integrin renders GSCs resistant to EGFR inhibition, which was overcome by FAK inhibition. Conclusions. These observations reveal a role for b1-integrin signaling through FAK in GSC treatment resistance and introduce self-assembling PAs as a novel new therapeutic approach for overcoming this resistance.
- Published
- 2013
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