TY - JOUR
T1 - Benzoquinone Ansamycin 17AAG Binds to Mitochondrial Voltage-Dependent Anion Channel and Inhibits Cell Invasion
AU - Xie, Qian
AU - Wondergem, Robert
AU - Shen, Yuehai
AU - Cavey, Greg
AU - Ke, Jiyuan
AU - Thompson, Ryan
AU - Bradley, Robert
AU - Daugherty-Holtrop, Jennifer
AU - Xu, Yong
AU - Chen, Edwin
AU - Omar, Hanan
AU - Rosen, Neal
AU - Wenkert, David
AU - Xu, H. Eric
AU - Vande Woud, George F.
PY - 2011/3/8
Y1 - 2011/3/8
N2 - 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.
AB - 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.
KW - benzoquinone ansamycin
KW - calcium regulation
UR - https://dc.etsu.edu/etsu-works/16367
UR - https://doi.org/10.1073/pnas.1015181108
U2 - 10.1073/pnas.1015181108
DO - 10.1073/pnas.1015181108
M3 - Article
VL - 108
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
ER -