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


METHODS
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.
Staverosky
Julia A
JA
Department of Biochemistry and Molecular Biology, Oregon Health &Science University, Portland, Oregon 97239, USA.
Muldoon
Leslie L
LL
Guo
Shuhua
S
Evans
Adam J
AJ
Neuwelt
Edward A
EA
Clinton
Gail M
GM
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007313:Insecta; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011923:Rats, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D066246:ErbB Receptors; D036341:Intercellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C434665:herstatin; C494918:AKT1 protein, human; C494920:Akt1 protein, rat