Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition

Maya Srikanth, Sunit Das, Eric J. Berns, Juno Kim, Samuel I Stupp, John A. Kessler

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

BackgroundGlioblastoma 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.

Original languageEnglish
Pages (from-to)319-329
Number of pages11
JournalNeuro-Oncology
Volume15
Issue number3
DOIs
Publication statusPublished - Mar 2013

Fingerprint

Nanofibers
Focal Adhesion Protein-Tyrosine Kinases
Epidermal Growth Factor Receptor
Glioma
Integrins
isoleucyl-lysyl-valyl-alanyl-valine
Valine
Peptides
Stem Cells
Apoptosis
Recurrence
Survival
Isoleucine
Glioblastoma
Alanine
Lysine
Fluorescent Antibody Technique
Epitopes
Therapeutics

Keywords

  • beta1-integrin
  • focal adhesion kinase
  • glioma stem-like cells
  • nanotechnology
  • treatment resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition. / Srikanth, Maya; Das, Sunit; Berns, Eric J.; Kim, Juno; Stupp, Samuel I; Kessler, John A.

In: Neuro-Oncology, Vol. 15, No. 3, 03.2013, p. 319-329.

Research output: Contribution to journalArticle

Srikanth, Maya ; Das, Sunit ; Berns, Eric J. ; Kim, Juno ; Stupp, Samuel I ; Kessler, John A. / Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition. In: Neuro-Oncology. 2013 ; Vol. 15, No. 3. pp. 319-329.
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N2 - BackgroundGlioblastoma 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.

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