Benzoquinone Ansamycin 17AAG Binds to Mitochondrial Voltage-Dependent Anion Channel and Inhibits Cell Invasion
Document Type
Article
Publication Date
3-8-2011
Description
Geldanamycin and its derivative 17AAG [17-(Allylamino)-17- demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca2+ mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca2+ and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca2+ concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.
Citation Information
Xie, Qian; Wondergem, Robert; Shen, Yuehai; Cavey, Greg; Ke, Jiyuan; Thompson, Ryan; Bradley, Robert; Daugherty-Holtrop, Jennifer; Xu, Yong; Chen, Edwin; Omar, Hanan; Rosen, Neal; Wenkert, David; Xu, H. Eric; and Vande Woud, George F.. 2011. Benzoquinone Ansamycin 17AAG Binds to Mitochondrial Voltage-Dependent Anion Channel and Inhibits Cell Invasion. Proceedings of the National Academy of Sciences of the United States of America. Vol.108(10). 4105-4110. https://doi.org/10.1073/pnas.1015181108 PMID: 21368131 ISSN: 0027-8424