Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 403, Issue 3-4, Pages 282-287Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2010.11.018
Keywords
Hsp90; Gambogic acid(GB); Inhibition; Client protein; NF-kappa B (NF-kappa B)
Categories
Funding
- National Natural Science Foundation of China [30973566, 30873148, 90913024]
- Natural Science Foundation of Fujian Province of China [2010J01227]
- Science and Technology Foundation of Xiamen [3502Z20093014]
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Gambogic acid (GB) is an important anti-cancer drug candidate, but the target protein by which it exerts its anti-cancer effects has not been identified. This study is the first to show that GB inhibits heat shock protein 90 (Hsp90) and down-regulates TNF-alpha/NF-kappa B in He La cells. The effects of GB on Hsp90 were studied by characterizing its physical interactions with Hsp90 upon binding, the noncompetitive inhibition of Hsp90 ATPase activity, and the degradation of Hsp90 client proteins (i.e., Akt, IKK) in HeLa cells. GB seems to bind to the N-terminal ATP-binding domain of Hsp90. Additionally, GB suppresses the activation of TNF-alpha/NF-kappa B and decreases XIAP expression levels and the ratio of Bcl-2/Bax, which in turn induces HeLa cell apoptosis. Thus, GB represents a promising therapeutic agent for cancer; it may also be useful as a probe to increase understanding of the biological functions of Hsp90. (C) 2010 Elsevier Inc. All rights reserved.
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