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Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells
The proteasome inhibitor bortezomib is an effective anti-cancer agent for the plasma cell malignancy multiple myeloma but clinical response is hindered by the emergence of drug resistance through unknown mechanisms. Drug sensitive myeloma cells were exposed to bortezomib to generate drug resistant c...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323002/ https://www.ncbi.nlm.nih.gov/pubmed/25481044 |
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author | Jaganathan, Sajjeev Malek, Ehsan Vallabhapurapu, Subrahmanya Vallabhapurapu, Sivakumar Driscoll, James J. |
author_facet | Jaganathan, Sajjeev Malek, Ehsan Vallabhapurapu, Subrahmanya Vallabhapurapu, Sivakumar Driscoll, James J. |
author_sort | Jaganathan, Sajjeev |
collection | PubMed |
description | The proteasome inhibitor bortezomib is an effective anti-cancer agent for the plasma cell malignancy multiple myeloma but clinical response is hindered by the emergence of drug resistance through unknown mechanisms. Drug sensitive myeloma cells were exposed to bortezomib to generate drug resistant cells that displayed a significant increase in subunits of the energy sensor AMP-activated protein kinase (AMPK). AMPK activity in resistant cells was increased and bortezomib resistant cells contained a ~4-fold greater level of autophagosomes than drug sensitive cells. Real-time measurements indicated that bortezomib reduced the oxygen consumption rate in drug sensitive cells more readily than in resistant cells. Genetic ablation of AMPK activity reduced the bortezomib effect on autophagy. The autophagy-related gene (Atg)5 is required for autophagosome formation and enhances cellular susceptibility to apoptotic stimuli. Atg5 knockout eliminated bortezomib-induced autophagosome formation and reduced susceptibility to bortezomib. Bortezomib treatment of myeloma cells lead to ATG5 cleavage through a calpain-dependent manner while calpain inhibition or a calpain-insensitive Atg5 mutant promoted bortezomib-resistance. In contrast, AICAR, an AMPK activator, enhanced bortezomib-induced cleavage of ATG5 and increased bortezomib-induced killing. Taken together, the results demonstrate that ATG5 cleavage provokes apoptosis and represents a molecular link between autophagy and apoptosis with therapeutic implications. |
format | Online Article Text |
id | pubmed-4323002 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-43230022015-02-10 Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells Jaganathan, Sajjeev Malek, Ehsan Vallabhapurapu, Subrahmanya Vallabhapurapu, Sivakumar Driscoll, James J. Oncotarget Research Paper The proteasome inhibitor bortezomib is an effective anti-cancer agent for the plasma cell malignancy multiple myeloma but clinical response is hindered by the emergence of drug resistance through unknown mechanisms. Drug sensitive myeloma cells were exposed to bortezomib to generate drug resistant cells that displayed a significant increase in subunits of the energy sensor AMP-activated protein kinase (AMPK). AMPK activity in resistant cells was increased and bortezomib resistant cells contained a ~4-fold greater level of autophagosomes than drug sensitive cells. Real-time measurements indicated that bortezomib reduced the oxygen consumption rate in drug sensitive cells more readily than in resistant cells. Genetic ablation of AMPK activity reduced the bortezomib effect on autophagy. The autophagy-related gene (Atg)5 is required for autophagosome formation and enhances cellular susceptibility to apoptotic stimuli. Atg5 knockout eliminated bortezomib-induced autophagosome formation and reduced susceptibility to bortezomib. Bortezomib treatment of myeloma cells lead to ATG5 cleavage through a calpain-dependent manner while calpain inhibition or a calpain-insensitive Atg5 mutant promoted bortezomib-resistance. In contrast, AICAR, an AMPK activator, enhanced bortezomib-induced cleavage of ATG5 and increased bortezomib-induced killing. Taken together, the results demonstrate that ATG5 cleavage provokes apoptosis and represents a molecular link between autophagy and apoptosis with therapeutic implications. Impact Journals LLC 2014-10-18 /pmc/articles/PMC4323002/ /pubmed/25481044 Text en Copyright: © 2014 Jaganathan 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 Jaganathan, Sajjeev Malek, Ehsan Vallabhapurapu, Subrahmanya Vallabhapurapu, Sivakumar Driscoll, James J. Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
title | Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
title_full | Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
title_fullStr | Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
title_full_unstemmed | Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
title_short | Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
title_sort | bortezomib induces ampk-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323002/ https://www.ncbi.nlm.nih.gov/pubmed/25481044 |
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