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CLU blocks HDACI-mediated killing of neuroblastoma

Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apop...

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Autores principales: Subramanian, Chitra, Jarzembowski, Jason A., Halsey, Sonja M., Kuick, Rork, Opipari, Anthony W., Castle, Valerie P., Kwok, Roland P. S.
Formato: Texto
Lenguaje:English
Publicado: Springer Netherlands 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041908/
https://www.ncbi.nlm.nih.gov/pubmed/21042904
http://dx.doi.org/10.1007/s13277-010-0120-y
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author Subramanian, Chitra
Jarzembowski, Jason A.
Halsey, Sonja M.
Kuick, Rork
Opipari, Anthony W.
Castle, Valerie P.
Kwok, Roland P. S.
author_facet Subramanian, Chitra
Jarzembowski, Jason A.
Halsey, Sonja M.
Kuick, Rork
Opipari, Anthony W.
Castle, Valerie P.
Kwok, Roland P. S.
author_sort Subramanian, Chitra
collection PubMed
description Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.
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spelling pubmed-30419082011-03-29 CLU blocks HDACI-mediated killing of neuroblastoma Subramanian, Chitra Jarzembowski, Jason A. Halsey, Sonja M. Kuick, Rork Opipari, Anthony W. Castle, Valerie P. Kwok, Roland P. S. Tumour Biol Research Article Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation. Springer Netherlands 2010-11-02 /pmc/articles/PMC3041908/ /pubmed/21042904 http://dx.doi.org/10.1007/s13277-010-0120-y Text en © The Author(s) 2010 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Research Article
Subramanian, Chitra
Jarzembowski, Jason A.
Halsey, Sonja M.
Kuick, Rork
Opipari, Anthony W.
Castle, Valerie P.
Kwok, Roland P. S.
CLU blocks HDACI-mediated killing of neuroblastoma
title CLU blocks HDACI-mediated killing of neuroblastoma
title_full CLU blocks HDACI-mediated killing of neuroblastoma
title_fullStr CLU blocks HDACI-mediated killing of neuroblastoma
title_full_unstemmed CLU blocks HDACI-mediated killing of neuroblastoma
title_short CLU blocks HDACI-mediated killing of neuroblastoma
title_sort clu blocks hdaci-mediated killing of neuroblastoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041908/
https://www.ncbi.nlm.nih.gov/pubmed/21042904
http://dx.doi.org/10.1007/s13277-010-0120-y
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