Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion.
Focal adhesion kinase (FAK) and hypoxia-inducible factor (HIF-1alpha) are both up-regulated in glioblastoma multiforme (GBMs), particularly in invasive zones. Because FAK may play an important role in the invasion of glioma cells into the surrounding brain, we sought an agent that causes down-regulation of FAK phosphorylation as a potential inhibitor of brain tumor invasion and growth. Geldanamycin (GA), a benzoquinone ansamycin antibiotic, binds to heat shock protein 90 (Hsp90) and interferes with its function. GA inhibits the proliferation of various non-glial cells and has anti-tumor activity. Moreover, GA blocks HIF-regulated transcription of VEGF and inhibits the VEGF-induced phosphorylation of FAK and migration of endothelial cells. Here, we tested the effect of GA on glioma cell migration in vitro and its potential to down-regulate HIF-1alpha induction. Our results demonstrate that GA (i) decreases U87MG, LN229, and U251MG glioma cell migration; (ii) reduces cell migration independent of p53 and PTEN status; (iii) prevents migration at non-toxic concentrations; (iv) reduces phosphorylation of FAK; and (v) inhibits cobalt chloride (CoCl(2))-mediated induction of HIF-1alpha in glioma cells. To the best of our knowledge, this is the first report showing that GA can inhibit phosphorylation of FAK concomitant with a decrease in cellular migration. One of the most clinically relevant aspects of this study is that GA interferes with the induction of HIF-1alpha that has been linked with glioma cell migration and angiogenesis. Given the fact that GA is a small lipophilic molecule capable of penetrating the blood brain barrier together with the data presented here provide a strong rationale for its use or its analogues in the treatment of highly invasive GBMs.
Zagzag
David
D
Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, USA. dz4@nyu.edu
Nomura
Motohiro
M
Friedlander
David R
DR
Blanco
C Y
CY
Gagner
Jean-Pierre
JP
Nomura
Naoko
N
Newcomb
Elizabeth W
EW
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D002465:Cell Movement / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005910:Glioma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D009361:Neoplasm Invasiveness; D009994:Osmolar Concentration; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D016326:Extracellular Matrix Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D011809:Quinones; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003035:Cobalt; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C018021:cobaltous chloride; C001277:geldanamycin