Cargando…
Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX
Inhibitors of the molecular chaperone heat shock protein 90 (HSP90) are of considerable current interest as targeted cancer therapeutic agents because of the ability to destabilize multiple oncogenic client proteins. Despite their resulting pleiotropic effects on multiple oncogenic pathways and hall...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875762/ https://www.ncbi.nlm.nih.gov/pubmed/24185264 |
_version_ | 1782297406398791680 |
---|---|
author | Powers, Marissa V Valenti, Melanie Miranda, Susana Maloney, Alison Eccles, Suzanne A. Thomas, George Clarke, Paul A Workman, Paul |
author_facet | Powers, Marissa V Valenti, Melanie Miranda, Susana Maloney, Alison Eccles, Suzanne A. Thomas, George Clarke, Paul A Workman, Paul |
author_sort | Powers, Marissa V |
collection | PubMed |
description | Inhibitors of the molecular chaperone heat shock protein 90 (HSP90) are of considerable current interest as targeted cancer therapeutic agents because of the ability to destabilize multiple oncogenic client proteins. Despite their resulting pleiotropic effects on multiple oncogenic pathways and hallmark traits of cancer, resistance to HSP90 inhibitors is possible and their ability to induce apoptosis is less than might be expected. Using an isogenic model for BAX knockout in HCT116 human colon carcinoma cells, we demonstrate the induction of BAX-dependent apoptosis at pharmacologically relevant concentrations of the HSP90 inhibitor 17-AAG both in vitro and in tumor xenografts in vivo. Removal of BAX expression by homologous recombination reduces apoptosis in vitro and in vivo but allows a lower level of cell death via a predominantly necrotic mechanism. Despite reducing apoptosis, the loss of BAX does not alter the overall sensitivity to 17-AAG in vitro or in vivo. The results indicate that 17-AAG acts predominantly to cause a cytostatic antiproliferative effect rather than cell death and further suggest that BAX status may not alter the overall clinical response to HSP90 inhibitors. Other agents may be required in combination to enhance tumor-selective killing by these promising drugs. In addition, there are implications for the use of apoptotic endpoints in the assessment of the activity of molecularly targeted agents. |
format | Online Article Text |
id | pubmed-3875762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-38757622014-01-07 Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX Powers, Marissa V Valenti, Melanie Miranda, Susana Maloney, Alison Eccles, Suzanne A. Thomas, George Clarke, Paul A Workman, Paul Oncotarget Research Paper Inhibitors of the molecular chaperone heat shock protein 90 (HSP90) are of considerable current interest as targeted cancer therapeutic agents because of the ability to destabilize multiple oncogenic client proteins. Despite their resulting pleiotropic effects on multiple oncogenic pathways and hallmark traits of cancer, resistance to HSP90 inhibitors is possible and their ability to induce apoptosis is less than might be expected. Using an isogenic model for BAX knockout in HCT116 human colon carcinoma cells, we demonstrate the induction of BAX-dependent apoptosis at pharmacologically relevant concentrations of the HSP90 inhibitor 17-AAG both in vitro and in tumor xenografts in vivo. Removal of BAX expression by homologous recombination reduces apoptosis in vitro and in vivo but allows a lower level of cell death via a predominantly necrotic mechanism. Despite reducing apoptosis, the loss of BAX does not alter the overall sensitivity to 17-AAG in vitro or in vivo. The results indicate that 17-AAG acts predominantly to cause a cytostatic antiproliferative effect rather than cell death and further suggest that BAX status may not alter the overall clinical response to HSP90 inhibitors. Other agents may be required in combination to enhance tumor-selective killing by these promising drugs. In addition, there are implications for the use of apoptotic endpoints in the assessment of the activity of molecularly targeted agents. Impact Journals LLC 2013-09-29 /pmc/articles/PMC3875762/ /pubmed/24185264 Text en Copyright: © 2013 Powers et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Research Paper Powers, Marissa V Valenti, Melanie Miranda, Susana Maloney, Alison Eccles, Suzanne A. Thomas, George Clarke, Paul A Workman, Paul Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX |
title | Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX |
title_full | Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX |
title_fullStr | Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX |
title_full_unstemmed | Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX |
title_short | Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX |
title_sort | mode of cell death induced by the hsp90 inhibitor 17-aag (tanespimycin) is dependent on the expression of pro-apoptotic bax |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875762/ https://www.ncbi.nlm.nih.gov/pubmed/24185264 |
work_keys_str_mv | AT powersmarissav modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT valentimelanie modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT mirandasusana modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT maloneyalison modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT ecclessuzannea modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT thomasgeorge modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT clarkepaula modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax AT workmanpaul modeofcelldeathinducedbythehsp90inhibitor17aagtanespimycinisdependentontheexpressionofproapoptoticbax |