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Herstatin, an Autoinhibitor of the Epidermal Growth Factor (EGF) Receptor Family, Blocks the Intracranial Growth of Glioblastoma

Departments of ¹ Biochemistry and Molecular Biology, ² Neurology, ³ Cell and Developmental Biology, and ⁴ Neurosurgery, Oregon Health &Science University and ⁵ Veterans Administration Medical Center, Portland, Oregon

Requests for reprints: Gail M. Clinton, Department of Biochemistry and Molecular Biology, L224, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-5626; Fax: 503-494-5627; E-mail: Clinton{at}ohsu.edu.

Purpose: Herstatin, an autoinhibitor of the epidermal growth factor (EGF) receptor family, was evaluated for efficacy against human glioblastoma in vitro and in vivo in a rat intracranial model.

Experimental Design: Glioblastoma controlled by EGF receptor (EGFR; U87MG) or by the truncated mutant, EGFR (U87MG/), were transfected with Herstatin and evaluated for in vitro and in vivo growth in nude rat brain. Cells treated with purified Herstatin in vitro were evaluated for growth and signal transduction.

Results: Herstatin expression prevented tumor formation by U87MG and purified Herstatin inhibited their growth in vitro in a dose-responsive fashion, whereas in vivo and in vitro growth of U87MG/ was resistant to Herstatin. Inhibition of U87MG growth correlated with suppressed EGF activation of EGFR and of Akt but not mitogen-activated protein kinase signaling pathways, whereas EGFR activity and intracellular signaling in U87MG/ were unaffected by Herstatin treatment.

Conclusions: Herstatin may have utility against glioblastoma driven by the EGFR but not the mutant EGFR. Blockade of Akt but not the mitogen-activated protein kinase signaling cascade appears to be critical for suppression of intracranial tumor growth.

Key Words: Epidermal Growth Factor Receptor • EGFR • Herstatin • Intracerebral Xenograft Model

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