Journal of the National Cancer Institute Advance Access originally published online on June 12, 2007
JNCI Journal of the National Cancer Institute 2007 99(12):949-961; doi:10.1093/jnci/djm007
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2007. Published by Oxford University Press.
ARTICLES |
Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin
Affiliations of authors: Departments of Thoracic/Head and Neck Medical Oncology, (SHO, JKW, WYK, QJ, WKH, HYL) and Head and Neck Surgery (YDY, JNM), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea (SSH, YGS, KWK); College of Pharmacy, Sungkyunkwan University, Suwon, Korea (HJP)
Correspondence to: Ho-Young Lee, PhD, Unit 432, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: hlee{at}mdanderson.org).
Background: The molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor 1
(HIF-1) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90.
Method: 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-1. All statistical tests were two-sided.
Results: Deguelin bound to the ATP-binding pocket of Hsp90 and disrupted Hsp90 function, leading to ubiquitin-mediated degradation of HIF-1. 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 mm3 and that of xenograft tumors treated with deguelin at 4 mg/kg was 115.9 mm3 (difference = 682.1 mm3, 95% confidence interval = 480.4 to 883.9 mm3; P<.001).
Conclusions: The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, which suppresses Hsp90 function.
| CONTEXT AND CAVEATS Prior knowledge
Heat shock protein 90 (Hsp90) is a molecular chaperone that is required for the stability and function of various normal proteins and oncoproteins (i.e., its client proteins), including hypoxia-inducible factor 1 Study design The molecular mechanism of action of deguelin was investigated in human xenograft mouse model systems for five different tumors and by computer modeling the binding of deguelin to the ATP-binding pocket of Hsp90. Contribution The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, which suppresses Hsp90 function. Implications Deguelin appears to be an effective antitumor agent that targets Hsp90. Complete and extensive screening for toxic effects in clinical trials is required before further development because of the wide expression of Hsp90 in normal tissues. Limitations Deguelin's mechanism of action on various Hsp90 client proteins has not been fully elucidated.
|
Manuscript received August 26, 2006; revised March 29, 2005; accepted May 9, 2007.
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 905.
This article has been cited by other articles:
|
|
 |
|
  G. Murillo, X. Peng, K. E.O. Torres, and R. G. Mehta Deguelin Inhibits Growth of Breast Cancer Cells by Modulating the Expression of Key Members of the Wnt Signaling Pathway Cancer Prevention Research, November 1, 2009; 2(11): 942 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Rodenberg and P. H. Brown A Novel Look into Estrogen Receptor-Negative Breast Cancer Prevention with the Natural, Multifunctional Signal Transduction Inhibitor Deguelin Cancer Prevention Research, November 1, 2009; 2(11): 915 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Woo, D. S. Choi, H. T. Tran, B. E. Gilbert, W. K. Hong, and H.-Y. Lee Liposomal Encapsulation of Deguelin: Evidence for Enhanced Antitumor Activity in Tobacco Carcinogen-Induced and Oncogenic K-ras-Induced Lung Tumorigenesis Cancer Prevention Research, April 1, 2009; 2(4): 361 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-Y. Kim, S. H. Oh, J.-K. Woo, W. K. Hong, and H.-Y. Lee Targeting Heat Shock Protein 90 Overrides the Resistance of Lung Cancer Cells by Blocking Radiation-Induced Stabilization of Hypoxia-Inducible Factor-1{alpha} Cancer Res., February 15, 2009; 69(4): 1624 - 1632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-Y. Kim, D. J. Chang, B. Hennessy, H. J. Kang, J. Yoo, S.-H. Han, Y.-S. Kim, H.-J. Park, S.-Y. Geo, G. Mills, et al. A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy Cancer Prevention Research, December 1, 2008; 1(7): 577 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Agarwal and G. Deep Kava, a Tonic for Relieving the Irrational Development of Natural Preventive Agents Cancer Prevention Research, November 1, 2008; 1(6): 409 - 412. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Balthasar, N. Bergelin, C. Lof, M. Vainio, S. Andersson, and K. Tornquist Interactions between sphingosine-1-phosphate and vascular endothelial growth factor signalling in ML-1 follicular thyroid carcinoma cells Endocr. Relat. Cancer, June 1, 2008; 15(2): 521 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Kassie, L. B. Anderson, L. Higgins, Y. Pan, I. Matise, M. Negia, P. Upadhyaya, M. Wang, and S. S. Hecht Chemopreventive agents modulate the protein expression profile of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo[a]pyrene-induced lung tumors in A/J mice Carcinogenesis, March 1, 2008; 29(3): 610 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Kim, J. H. Kim, Y. S. Yu, K. H. Park, H. J. Kang, H.-Y. Lee, and K.-W. Kim Antiangiogenic Effect of Deguelin on Choroidal Neovascularization J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 643 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Jin, L. Feng, C. Behrens, B. N. Bekele, I. I. Wistuba, W.-K. Hong, and H.-Y. Lee Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin Cancer Res., December 15, 2007; 67(24): 11630 - 11639. [Abstract] [Full Text] [PDF]
|
|