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J. Biol. Chem., Vol. 283, Issue 25, 17184-17193, June 20, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/25/17184    most recent M709447200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chen, W.-Y. Articles by Wu, C.-C. PubMed PubMed Citation Articles by Chen, W.-Y. Articles by Wu, C.-C. Social Bookmarking                      What's this?

Tubocapsenolide A, a Novel Withanolide, Inhibits Proliferation and Induces Apoptosis in MDA-MB-231 Cells by Thiol Oxidation of Heat Shock Proteins^*

Wen-Ying Chen, Fang-Rong Chang, Zih-You Huang, Jyun-Hong Chen, Yang-Chang Wu¹, and Chin-Chung Wu²

From the Graduate Institute of Natural Products, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan and Basic Medical Science Education Center, Fooyin University, Kaohsiung 831, Taiwan

Tubocapsenolide A (TA), a novel withanolide-type steroid, exhibits potent cytotoxicity against several human cancer cell lines. In the present study, we observed that treatment of human breast cancer MDA-MB-231 cells with TA led to cell cycle arrest at G₁ phase and apoptosis. The actions of TA were correlated with proteasome-dependent degradation of Cdk4, cyclin D1, Raf-1, Akt, and mutant p53, which are heat shock protein 90 (Hsp90) client proteins. TA treatment induced a transient increase in reactive oxygen species and a decrease in the intracellular glutathione contents. Nonreducing SDS-PAGE revealed that TA rapidly and selectively induced thiol oxidation and aggregation of Hsp90 and Hsp70, both in intact cells and in cell-free systems using purified recombinant proteins. Furthermore, TA inhibited the chaperone activity of Hsp90-Hsp70 complex in the luciferase refolding assay. N-Acetylcysteine, a thiol antioxidant, prevented all of the TA-induced effects, including oxidation of heat shock proteins, degradation of Hsp90 client proteins, and apoptosis. In contrast, non-thiol antioxidants (trolox and vitamin C) were ineffective to prevent Hsp90 inhibition and cell death. Taken together, our results demonstrate that the TA inhibits the activity of Hsp90-Hsp70 chaperone complex, at least in part, by a direct thiol oxidation, which in turn leads to the destabilization and depletion of Hsp90 client proteins and thus causes cell cycle arrest and apoptosis in MDA-MB-231 cells. Therefore, TA can be considered as a new type of inhibitor of Hsp90-Hsp70 chaperone complex, which has the potential to be developed as a novel strategy for cancer treatment.

Received for publication, November 19, 2007 , and in revised form, April 24, 2008.

^* This work was supported by National Science Council of Taiwan Grant NSC 95-2320-B-037-039-MY2. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. Tel.: 886-7-3121101 (ext. 2197); Fax: 886-7-3114773; E-mail: yachwu{at}kmu.edu.tw. ² To whom correspondence may be addressed. Tel.: 886-7-3121101 (ext. 2669); Fax: 886-7-3114773; E-mail: ccwu{at}kmu.edu.tw.

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