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 ?1-integrin signaling as one such potential target.

Methods

We used GSCs isolated from primary human gliomas and maintained in stem cell conditions. We manipulated ?1-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 ?1-integrin expression correlates with decreased survival in glioma patients and that ?1-integrin is highly expressed by GSCs. The IKVAV PA potently increases immobilized ?1-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 ?1-integrin renders GSCs resistant to EGFR inhibition, which was overcome by FAK inhibition.

Conclusions

These observations reveal a role for ?1-integrin signaling through FAK in GSC treatment resistance and introduce self-assembling PAs as a novel new therapeutic approach for overcoming this resistance.

SUBMITTER: Srikanth M 

PROVIDER: S-EPMC3578490 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature