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Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response

Mitochondrial functions play a central role in energy metabolism and provide survival fitness to both normal and tumor cells. Mitochondrial chaperonin Hsp60 is involved in both pro- and anti-apoptotic functions, but how Hsp60 senses the mitochondria selective oxidative stress response is unknown. In...

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Autores principales: Sarangi, Upasana, Singh, Manish Kumar, Abhijnya, Kanugovi Vijaya Vittal, Reddy, Lebaka Prasanna Anjaneya, Prasad, Badabagni Siva, Pitke, Vikrant Vinay, Paithankar, Khanderao, Sreedhar, Amere Subbarao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Libertas Academica 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767580/
https://www.ncbi.nlm.nih.gov/pubmed/24027419
http://dx.doi.org/10.4137/DTI.S12513
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author Sarangi, Upasana
Singh, Manish Kumar
Abhijnya, Kanugovi Vijaya Vittal
Reddy, Lebaka Prasanna Anjaneya
Prasad, Badabagni Siva
Pitke, Vikrant Vinay
Paithankar, Khanderao
Sreedhar, Amere Subbarao
author_facet Sarangi, Upasana
Singh, Manish Kumar
Abhijnya, Kanugovi Vijaya Vittal
Reddy, Lebaka Prasanna Anjaneya
Prasad, Badabagni Siva
Pitke, Vikrant Vinay
Paithankar, Khanderao
Sreedhar, Amere Subbarao
author_sort Sarangi, Upasana
collection PubMed
description Mitochondrial functions play a central role in energy metabolism and provide survival fitness to both normal and tumor cells. Mitochondrial chaperonin Hsp60 is involved in both pro- and anti-apoptotic functions, but how Hsp60 senses the mitochondria selective oxidative stress response is unknown. In this study, by using rotenone, an irreversible inhibitor of oxidative phosphorylation against IMR-32 and BC-8 tumor cells containing differential heat shock transcriptional machinery, we studied whether the oxidative stress response is related to Hsp60. The accelerated cytotoxicity in response to rotenone has been correlated with enhanced production of O(2)(•−), H(2)O(2), reactive oxygen species, and Hsp60 translocation from the mitochondria to the cytoplasm. The inability of cells to resist oxidative stress mediated Hsp60 translocation appeared to depend on mitochondrial oxyradical scavenging system and Bax translocation. A delayed oxidative stress response in hsp60 shRNA-treated cells was found to be due to increased mitochondrial translocation of Hsp60 on shRNA pre-sensitization. Overexpression of Hsp60 failed to protect cells from oxidative stress due to a lack of its mitochondrial retention upon post-rotenone treatment. These results also revealed that Hsp60 mitochondrial localization is indispensable for decreasing O(2)(•−) levels, but not H(2)O(2) and ROS levels. However, cycloheximide treatment alone induced Hsp60 translocation, while rotenone combination delayed this translocation. In contrast to oxidative stress, MG132 and 17AAG treatments showed mitochondrial retention of Hsp60; however, MG132 combination either with hsp60 shRNA or 17AAG induced its translocation. Additionally, overexpression of Huntingtin gene also resulted in Hsp60 mitochondrial accumulation. We suggest that Hsp60 may act as a barrier to pharmacological targeting of mitochondria.
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spelling pubmed-37675802013-09-11 Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response Sarangi, Upasana Singh, Manish Kumar Abhijnya, Kanugovi Vijaya Vittal Reddy, Lebaka Prasanna Anjaneya Prasad, Badabagni Siva Pitke, Vikrant Vinay Paithankar, Khanderao Sreedhar, Amere Subbarao Drug Target Insights Original Research Mitochondrial functions play a central role in energy metabolism and provide survival fitness to both normal and tumor cells. Mitochondrial chaperonin Hsp60 is involved in both pro- and anti-apoptotic functions, but how Hsp60 senses the mitochondria selective oxidative stress response is unknown. In this study, by using rotenone, an irreversible inhibitor of oxidative phosphorylation against IMR-32 and BC-8 tumor cells containing differential heat shock transcriptional machinery, we studied whether the oxidative stress response is related to Hsp60. The accelerated cytotoxicity in response to rotenone has been correlated with enhanced production of O(2)(•−), H(2)O(2), reactive oxygen species, and Hsp60 translocation from the mitochondria to the cytoplasm. The inability of cells to resist oxidative stress mediated Hsp60 translocation appeared to depend on mitochondrial oxyradical scavenging system and Bax translocation. A delayed oxidative stress response in hsp60 shRNA-treated cells was found to be due to increased mitochondrial translocation of Hsp60 on shRNA pre-sensitization. Overexpression of Hsp60 failed to protect cells from oxidative stress due to a lack of its mitochondrial retention upon post-rotenone treatment. These results also revealed that Hsp60 mitochondrial localization is indispensable for decreasing O(2)(•−) levels, but not H(2)O(2) and ROS levels. However, cycloheximide treatment alone induced Hsp60 translocation, while rotenone combination delayed this translocation. In contrast to oxidative stress, MG132 and 17AAG treatments showed mitochondrial retention of Hsp60; however, MG132 combination either with hsp60 shRNA or 17AAG induced its translocation. Additionally, overexpression of Huntingtin gene also resulted in Hsp60 mitochondrial accumulation. We suggest that Hsp60 may act as a barrier to pharmacological targeting of mitochondria. Libertas Academica 2013-09-01 /pmc/articles/PMC3767580/ /pubmed/24027419 http://dx.doi.org/10.4137/DTI.S12513 Text en © 2013 the author(s), publisher and licensee Libertas Academica Ltd. This is an open access article published under the Creative Commons CC-BY-NC 3.0 license.
spellingShingle Original Research
Sarangi, Upasana
Singh, Manish Kumar
Abhijnya, Kanugovi Vijaya Vittal
Reddy, Lebaka Prasanna Anjaneya
Prasad, Badabagni Siva
Pitke, Vikrant Vinay
Paithankar, Khanderao
Sreedhar, Amere Subbarao
Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response
title Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response
title_full Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response
title_fullStr Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response
title_full_unstemmed Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response
title_short Hsp60 Chaperonin Acts as Barrier to Pharmacologically Induced Oxidative Stress Mediated Apoptosis in Tumor Cells with Differential Stress Response
title_sort hsp60 chaperonin acts as barrier to pharmacologically induced oxidative stress mediated apoptosis in tumor cells with differential stress response
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767580/
https://www.ncbi.nlm.nih.gov/pubmed/24027419
http://dx.doi.org/10.4137/DTI.S12513
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