Abstract
BACKGROUND: Receptors of the ErbB family are involved in the development of various cancers, and the inhibition of these receptors represents an attractive therapeutic concept. Upon ligand binding, ErbB receptors become activated as homo- or heterodimers, leading to the activation of downstream signaling cascades that result in the facilitation of cell proliferation and migration. A region of the extracellular part of the receptor, termed the 'dimerization arm', is important for the formation of receptor dimers and represents an attractive target for the design of ErbB inhibitors. METHODS: An ErbB1 targeting peptide, termed Herfin-1, was designed based on a model of the tertiary structure of the EGF-EGFR ternary complex. The binding kinetics of this peptide were determined employing surface plasmon resonance analyses. ErbB1-4 expression and phosphorylation in human glioblastoma cell lines U87 and U118 were determined by Western blotting using specific antibodies. Cell proliferation was determined by MTS staining. Cell migration was examined using a Chemotaxis Migration Kit. Neurite outgrowth from primary cerebellar granule neurons was evaluated by fluorescence microscopy and image processing. RESULTS: The present study shows that Herfin-1 functions as an ErbB1 antagonist. It binds to the extracellular domain of ErbB1 with a KD value of 361 nM. In U87 and U118 cells, both expressing high levels of ErbB1, Herfin-1 inhibits EGF-induced ErbB1 phosphorylation and cell migration. Additionally, Herfin-1 was found to increase neurite outgrowth in cerebellar granule neurons, likely through the inhibition of a sustained weak ErbB1 activation. CONCLUSIONS: Targeting the ErbB1 receptor dimerization interface is a promising strategy to inhibit receptor activation in ErbB1-expressing glioma cells.