Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion Journal Article
| Authors: | Xie, Q.; Wondergem, R.; Shen, Y.; Cavey, G.; Ke, J.; Thompson, R.; Bradley, R.; Daugherty-Holtrop, J.; Xu, Y.; Chen, E.; Omar, H.; Rosen, N.; Wenkert, D.; Xu, H. E.; Vande Woud, G. F. |
| Article Title: | Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion |
| Abstract: | 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. |
| Keywords: | controlled study; nonhuman; enzyme activity; cell membrane; heat shock protein 90; mitochondrial membrane; cell invasion; drug binding; urokinase; geldanamycin; radicicol; calcium ion; hydrophobicity; ansamycin derivative; benzoquinone ansamycin; calcium regulation; benzoquinone; telatinib; ubiquinone derivative; voltage dependent anion channel |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 108 |
| Issue: | 10 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2011-03-08 |
| Start Page: | 4105 |
| End Page: | 4110 |
| Language: | English |
| DOI: | 10.1073/pnas.1015181108 |
| PROVIDER: | scopus |
| PMCID: | PMC3053964 |
| PUBMED: | 21368131 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 23 June 2011" - "CODEN: PNASA" - "Source: Scopus" |
