Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin
Open Access
- 12 June 2007
- journal article
- research article
- Published by Oxford University Press (OUP) in JNCI Journal of the National Cancer Institute
- Vol. 99 (12), 949-961
- https://doi.org/10.1093/jnci/djm007
Abstract
The molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor 1α (HIF-1α) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90. Human xenograft tumors were generated in mice from H1299 (n = 6 per group) and A549 (n = 4 per group) non–small-cell lung cancer cells, UMSCC38 (n = 5 per group) head and neck cancer cells, MKN45 (n = 5 per group) stomach cancer cells, and PC-3 (n = 3 per group) prostate cancer cells. Tumor-bearing mice were treated with deguelin at 4 or 8 mg/kg or with vehicle (as a control) twice a day by oral gavage for 15–28 days. Protein expression was assessed by western blot analysis. Akt and Hsp90 were assessed by use of adenoviral vectors expressing constitutively active Akt or Hsp90. Binding of deguelin to Hsp90 was examined by docking analysis and by competition binding experiments with ATP–Sepharose beads. The proteasome inhibitor MG132 was used to investigate deguelin's effect on the induction of ubiquitin-mediated proteasomal degradation of HIF-1α. All statistical tests were two-sided. Deguelin bound to the ATP-binding pocket of Hsp90 and disrupted Hsp90 function, leading to ubiquitin-mediated degradation of HIF-1α. Administration of deguelin to xenograft-bearing mice statistically significantly decreased tumor growth by inducing apoptosis and decreasing the expression of Hsp90 client proteins, without detectable toxic effects. For example, at 15 days after the start of deguelin treatment, the volume of untreated control H1299 xenograft tumors was 798 mm 3 and that of xenograft tumors treated with deguelin at 4 mg/kg was 115.9 mm 3 (difference = 682.1 mm 3 , 95% confidence interval = 480.4 to 883.9 mm 3 ; P <.001). The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, which suppresses Hsp90 function.Keywords
This publication has 52 references indexed in Scilit:
- Antileukemic Activity of Shepherdin and Molecular Diversity of Hsp90 InhibitorsJNCI Journal of the National Cancer Institute, 2006
- Her2-Targeted Therapies in Non–Small Cell Lung CancerClinical Cancer Research, 2006
- Inhibitors of the HSP90 Molecular Chaperone: Current StatusAdvances in Cancer Research, 2006
- Chemopreventive Effects of Deguelin, a Novel Akt Inhibitor, on Tobacco-Induced Lung TumorigenesisJNCI Journal of the National Cancer Institute, 2005
- Hypoxia-inducible Factor 1α and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract CancerJNCI Journal of the National Cancer Institute, 2005
- Molecular mechanisms of deguelin-induced apoptosis in transformed human bronchial epithelial cellsBiochemical Pharmacology, 2004
- Heat shock protein 90Current Opinion in Oncology, 2003
- Pharmacokinetics of deguelin, a cancer chemopreventive agent in ratsCancer Chemotherapy and Pharmacology, 2001
- Induction of Heat-Shock Protein Synthesis and Thermotolerance in EL-4 Ascites Tumor Cells by Transient ATP Depletion after Ischemic StressExperimental and Molecular Pathology, 1994
- Chapter 8 Use of Recombinant Adenovirus for Metabolic Engineering of Mammalian CellsMethods in cell biology, 1994