HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Summary Full Text Full Text (PDF) All Versions of this Article: fj.05-5665fjev1 20/12/2147    most recent Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lei, X. Articles by Chen, Q. Search for Related Content PubMed PubMed Citation Articles by Lei, X. Articles by Chen, Q.

Gossypol induces Bax/Bak-independent activation of apoptosis and cytochrome c release via a conformational change in Bcl-2

Xiaobo Lei^*,,1, Yingyu Chen^*,,1, Guanhua Du, Wenyu Yu^||, Xiaohui Wang^*, Hong Qu^||, Bin Xia^||, Hongping He^¶, Jianhua Mao^*, Weixing Zong^#, Xudong Liao^*, Maryam Mehrpour^*,**, Xiaojiang Hao^¶ and Quan Chen^*,2

^* The Laboratory of Apoptosis and Cancer Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, P.R. China;

Graduate School of the Chinese Academy of Sciences, Beijing, P.R. China;

Center for Human Disease Genomics, Peking University, Beijing, P.R. China;

Institute of Materia Medica, Academy Medical Science and Peking Union Medical College, Beijing, P.R. China;.

^|| College of Life Sciences, Peking University, Beijing, P.R. China;

^¶ The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Beijing, P.R. China;

^# Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA;

^** INSERM U-487, Laboratoire de Cytokines et Immunologie des tumeurs Humaines, Institut Gustave Roussy PR1 and IFR 54, Villejuif, France

²Correspondence: The Laboratory of Apoptosis and Cancer Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Bei Si Huan Xi Road 25, Haidian District, Beijing 100080, P.R. China. E-mail: chenq{at}ioz.ac.cn

ABSTRACT

Cells without Bak and Bax are largely resistant to apoptosis (1;2), despite the presence of other key components of the apoptotic machinery. We screened 7,800 natural compounds and found several that could specifically induce caspase activation and the release of cytochrome c (cyto c) in the bak^–/–/bax^–/– cells. One of these was gossypol, a polyphenolic compound naturally found in cottonseed that has been used in antifertility trials. We found that gossypol, but not other Bcl-2-interacting molecules, induced cyto c release and loss of mitochondrial membrane potential (m) independently of mPTP and Bak/Bax activation. Furthermore, we found that gossypol induced an allosteric change in Bcl-2 in both bak^–/–/bax^–/– cells and Bcl-2 overexpressing cells. This change in Bcl-2 conformation led to the release of cyto c in the presence of Bcl-2 and Bcl-xL in reconstituted proteoliposomes. We also observed that gossypol substantially reduced the growth of tumor xenografts from Bcl-2 overexpressing cells in nude mice. We conclude that gossypol converts the antiapoptotic molecule Bcl-2 into a proapoptotic molecule that can mediate the release of cyto c and induce apoptosis—Lei, X., Chen, Y., Du, G., Yu, W., Wang, X., Qu, H., Xia, B., He, H., Mao, J., Zong, W., Liao, X., L., Mehrpour, M., Hao, X., Chen, Q. Gossypol induces Bax/Bak-independent activation of apoptosis and cytochrome c release via a conformational change in Bcl-2.

This article has been cited by other articles:

				K. Balakrishnan, W. G. Wierda, M. J. Keating, and V. Gandhi Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells Blood, September 1, 2008; 112(5): 1971 - 1980. [Abstract] [Full Text] [PDF]

				K. F. Wan, S.-L. Chan, S. K. Sukumaran, M.-C. Lee, and V. C. Yu Chelerythrine Induces Apoptosis through a Bax/Bak-independent Mitochondrial Mechanism J. Biol. Chem., March 28, 2008; 283(13): 8423 - 8433. [Abstract] [Full Text] [PDF]