Induction of the Hypoxia-Inducible Factor System by Low Levels of Heat Shock Protein 90 Inhibitors
| Autor: | Renato Wirthner, Dörthe M. Katschinski, Nadia O. Ibrahim, Corinna Franke, Daniel P. Stiehl, Torsten Hahn, Roland H. Wenger |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Angiogenesis Lactams Macrocyclic Gene Expression Neovascularization Physiologic Chick Embryo Pharmacology Biology Chorioallantoic Membrane chemistry.chemical_compound Heat shock protein Benzoquinones Animals Humans HSP90 Heat-Shock Proteins Cell Nucleus Antibiotics Antineoplastic Dose-Response Relationship Drug Quinones Geldanamycin Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Hsp90 Vascular endothelial growth factor Rifabutin Oncology Hypoxia-inducible factors chemistry Tumor progression biology.protein Protein stabilization HeLa Cells |
| Zdroj: | Cancer Research. 65:11094-11100 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-05-1877 |
| Popis: | The heterodimeric hypoxia-inducible factor-1 (HIF-1) is involved in key steps of tumor progression and therapy resistance and thus represents an attractive antitumor target. Because heat shock protein 90 (HSP90) plays an important role in HIF-1α protein stabilization and because HSP90 inhibitors are currently being tested in clinical phase I trials for anticancer treatment, we investigated their role as anti-HIF-1α agents. Surprisingly, low-dose (5-30 nmol/L) treatment of HeLa cells with three different HSP90 inhibitors (17-AAG, 17-DMAG, and geldanamycin) increased HIF-1–dependent reporter gene activity, whereas higher doses (1-3 μmol/L) resulted in a reduction of hypoxia-induced HIF-1 activity. In line with these data, low-dose treatment with HSP90 inhibitors increased and high-dose treatment reduced hypoxic HIF-1α protein levels, respectively. HIF-1α protein stabilized by HSP90 inhibitors localized to the nucleus. As a result of HSP90-modulated HIF-1 activity, the levels of the tumor-relevant HIF-1 downstream targets carbonic anhydrase IX, prolyl-4-hydroxylase domain protein 3, and vascular endothelial growth factor were increased or decreased after low-dose or high-dose treatment, respectively. Bimodal effects of 17-AAG on vessel formation were also seen in the chick chorioallantoic membrane angiogenesis assay. In summary, these results suggest that dosage will be a critical factor in the treatment of tumor patients with HSP90 inhibitors. |
| Databáze: | OpenAIRE |
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