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Targeting Glutathione S-transferase M4 in Ewing sarcoma
Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5-year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123608/ https://www.ncbi.nlm.nih.gov/pubmed/25147782 http://dx.doi.org/10.3389/fped.2014.00083 |
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author | Zhuo, Rupeng Kosak, Kenneth M. Sankar, Savita Wiles, Elizabeth T. Sun, Ying Zhang, Jianxing Ayello, Janet Prestwich, Glenn D. Shami, Paul J. Cairo, Mitchell S. Lessnick, Stephen L. Luo, Wen |
author_facet | Zhuo, Rupeng Kosak, Kenneth M. Sankar, Savita Wiles, Elizabeth T. Sun, Ying Zhang, Jianxing Ayello, Janet Prestwich, Glenn D. Shami, Paul J. Cairo, Mitchell S. Lessnick, Stephen L. Luo, Wen |
author_sort | Zhuo, Rupeng |
collection | PubMed |
description | Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5-year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that high expression of glutathione S-transferase M4 (GSTM4) in primary tumors correlates with poor patient outcomes. GSTM4 is required for oncogenic transformation and mediates resistance to chemotherapeutic drugs in Ewing sarcoma cells. Here, we performed RNA-sequencing analyses of Ewing sarcoma cells and combined our results with publicly available datasets to demonstrate that GSTM4 is a major GST specifically expressed in Ewing sarcoma. Pharmacological inhibition of GSTM4 activity using a pan GST inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), significantly limited cellular proliferation and oncogenic transformation of Ewing sarcoma cells. Moreover, combined use of NBDHEX and etoposide synergistically increased cytotoxicity, suggesting a role for GSTM4 as an inhibitor of apoptosis. Mechanistic studies revealed that GSTM4 limits apoptosis owing to its ability to interact with Apoptosis Signal-regulating Kinase 1 (ASK1) and inhibit signaling via the c-Jun N-terminal Kinase axis. To exploit our observation that GSTM4 expression is specifically up-regulated in Ewing sarcoma, we tested the effect of a GSTM4-activated anti-cancer agent, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K, on tumor growth and survival. We found that JS-K robustly decreased Ewing sarcoma cell viability and xenograft tumor growth and improved overall survival of xenograft mice. Our data suggest that GSTM4 is a novel therapeutic target for the treatment of high GSTM4-expressing Ewing sarcoma. Strategies that combine standard chemotherapy with agents that inhibit GSTM4, that are activated by GSTM4, or that block GSTM4/ASK1 interactions, can potentially be more specific and/or efficacious than standard therapeutic approaches. |
format | Online Article Text |
id | pubmed-4123608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-41236082014-08-21 Targeting Glutathione S-transferase M4 in Ewing sarcoma Zhuo, Rupeng Kosak, Kenneth M. Sankar, Savita Wiles, Elizabeth T. Sun, Ying Zhang, Jianxing Ayello, Janet Prestwich, Glenn D. Shami, Paul J. Cairo, Mitchell S. Lessnick, Stephen L. Luo, Wen Front Pediatr Pediatrics Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5-year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that high expression of glutathione S-transferase M4 (GSTM4) in primary tumors correlates with poor patient outcomes. GSTM4 is required for oncogenic transformation and mediates resistance to chemotherapeutic drugs in Ewing sarcoma cells. Here, we performed RNA-sequencing analyses of Ewing sarcoma cells and combined our results with publicly available datasets to demonstrate that GSTM4 is a major GST specifically expressed in Ewing sarcoma. Pharmacological inhibition of GSTM4 activity using a pan GST inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), significantly limited cellular proliferation and oncogenic transformation of Ewing sarcoma cells. Moreover, combined use of NBDHEX and etoposide synergistically increased cytotoxicity, suggesting a role for GSTM4 as an inhibitor of apoptosis. Mechanistic studies revealed that GSTM4 limits apoptosis owing to its ability to interact with Apoptosis Signal-regulating Kinase 1 (ASK1) and inhibit signaling via the c-Jun N-terminal Kinase axis. To exploit our observation that GSTM4 expression is specifically up-regulated in Ewing sarcoma, we tested the effect of a GSTM4-activated anti-cancer agent, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K, on tumor growth and survival. We found that JS-K robustly decreased Ewing sarcoma cell viability and xenograft tumor growth and improved overall survival of xenograft mice. Our data suggest that GSTM4 is a novel therapeutic target for the treatment of high GSTM4-expressing Ewing sarcoma. Strategies that combine standard chemotherapy with agents that inhibit GSTM4, that are activated by GSTM4, or that block GSTM4/ASK1 interactions, can potentially be more specific and/or efficacious than standard therapeutic approaches. Frontiers Media S.A. 2014-08-06 /pmc/articles/PMC4123608/ /pubmed/25147782 http://dx.doi.org/10.3389/fped.2014.00083 Text en Copyright © 2014 Zhuo, Kosak, Sankar, Wiles, Sun, Zhang, Ayello, Prestwich, Shami, Cairo, Lessnick and Luo. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pediatrics Zhuo, Rupeng Kosak, Kenneth M. Sankar, Savita Wiles, Elizabeth T. Sun, Ying Zhang, Jianxing Ayello, Janet Prestwich, Glenn D. Shami, Paul J. Cairo, Mitchell S. Lessnick, Stephen L. Luo, Wen Targeting Glutathione S-transferase M4 in Ewing sarcoma |
title | Targeting Glutathione S-transferase M4 in Ewing sarcoma |
title_full | Targeting Glutathione S-transferase M4 in Ewing sarcoma |
title_fullStr | Targeting Glutathione S-transferase M4 in Ewing sarcoma |
title_full_unstemmed | Targeting Glutathione S-transferase M4 in Ewing sarcoma |
title_short | Targeting Glutathione S-transferase M4 in Ewing sarcoma |
title_sort | targeting glutathione s-transferase m4 in ewing sarcoma |
topic | Pediatrics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123608/ https://www.ncbi.nlm.nih.gov/pubmed/25147782 http://dx.doi.org/10.3389/fped.2014.00083 |
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