Herstatin, an autoinhibitor of the epidermal growth factor receptor family, blocks the intracranial growth of glioblastoma.

Abstract

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, DeltaEGFR (U87MG/Delta), 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/Delta 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 DeltaEGFR activity and intracellular signaling in U87MG/Delta were unaffected by Herstatin treatment.

CONCLUSIONS:

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

• Authors: Julia A Staverosky, Leslie L Muldoon, Shuhua Guo, Adam J Evans, Edward A Neuwelt, Gail M Clinton
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 1 Pg. 335-40 (Jan 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15671564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Intercellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins
• herstatin
• ErbB Receptors
• Receptor, ErbB-2
• AKT1 protein, human
• Akt1 protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Blotting, Western
• Brain (metabolism)
• Brain Neoplasms (metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Dose-Response Relationship, Drug
• ErbB Receptors (metabolism)
• Female
• Glioblastoma (drug therapy, metabolism)
• Humans
• Immunohistochemistry
• In Vitro Techniques
• Insecta
• Intercellular Signaling Peptides and Proteins (metabolism, pharmacology)
• Neoplasm Transplantation
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Rats
• Rats, Nude
• Receptor, ErbB-2 (metabolism)
• Signal Transduction
• Time Factors
• Transfection