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Induction of the Hypoxia-Inducible Factor System by Low Levels of Heat Shock Protein 90 Inhibitors

¹ Cell Physiology Group, Medical Faculty, Martin Luther University Halle, Halle, Germany and ² Institute of Physiology, University of Zürich, and Center for Integrative Human Physiology, Zürich, Switzerland

Requests for reprints: Dörthe M. Katschinski, Cell Physiology, Martin Luther University Halle, Magdeburger Str. 2, D-06097 Halle, Germany. Phone: 49-345-557-1374; Fax: 49-345-557-1378; E-mail: doerthe.katschinski{at}medizin.uni-halle.de.

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-1 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-1 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-1 protein levels, respectively. HIF-1 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.

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