title: 17AEP-GA, an HSP90 antagonist, is a potent inhibitor of glioblastoma             cell proliferation, survival, migration and invasion.
abstract: Glioblastoma multiforme (GBM) is the most frequent and the most malignant human brain tumor. The expression of receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is strongly increased in GBM, where they promote tumor proliferation, cell survival, migration, invasion and angiogenesis. We used geldanamycins (GAs) (inhibitors of HSP90) in order to block glioblastoma growth and HGF-dependent cell migration and invasion. The effect of GAs on three GBM cell lines was tested and we found their antiproliferative effect on tumor cells. The maximum level of inhibition reached 70%. After treatment with GAs, cells also became apoptotic as determined by Annexin V-positive staining and activation of the caspase-3 pathway. We examined the expression and activity of the MET receptor on GBM cell lines and we observed phosphorylation of AKT and MAPK after HGF stimulation by western blot analysis. Since GBM cells express high level of MET receptor and were shown to respond to HGF by increased motility we tested if GAs could negatively affect GBM cell movement. In our study, we found that GAs inhibited the chemotaxis of glioblastoma cells toward the hepatocyte growth factor gradient. The GAs also blocked migration of tumor cells through a Matrigel layer in invasion assays. The strongest inhibitory effect was observed for GA and its analog, 17AEP-GA. Based on our results, GAs, particularly 17AEP-GA, could be considered as a new potential agent to treat glioblastoma multiforme.
authors.affiliation: Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University School of Medicine, Cracow, Poland. kmiekus@cm-uj.krakow.pl
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Miekus
authors.forename: Jacek
authors.initials: J
authors.lastname: Kijowski
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Sekuła
authors.forename: Marcin
authors.initials: M
authors.lastname: Majka
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects / Q000378:metabolism
chemical_list: C548185:17-(2-(pyrrolidin-1-yl)ethyl)-amino-17-demethoxygeldanamycin; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C001277:geldanamycin