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BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling
We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593608/ https://www.ncbi.nlm.nih.gov/pubmed/28915637 http://dx.doi.org/10.18632/oncotarget.18096 |
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author | Gu, Chunyan Peng, Hailin Lu, Yue Yang, Hongbao Tian, Zhidan Yin, Gang Zhang, Wen Lu, Sicheng Zhang, Yi Yang, Ye |
author_facet | Gu, Chunyan Peng, Hailin Lu, Yue Yang, Hongbao Tian, Zhidan Yin, Gang Zhang, Wen Lu, Sicheng Zhang, Yi Yang, Ye |
author_sort | Gu, Chunyan |
collection | PubMed |
description | We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro. Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo. Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM. |
format | Online Article Text |
id | pubmed-5593608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-55936082017-09-14 BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling Gu, Chunyan Peng, Hailin Lu, Yue Yang, Hongbao Tian, Zhidan Yin, Gang Zhang, Wen Lu, Sicheng Zhang, Yi Yang, Ye Oncotarget Research Paper We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro. Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo. Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM. Impact Journals LLC 2017-05-23 /pmc/articles/PMC5593608/ /pubmed/28915637 http://dx.doi.org/10.18632/oncotarget.18096 Text en Copyright: © 2017 Gu et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Gu, Chunyan Peng, Hailin Lu, Yue Yang, Hongbao Tian, Zhidan Yin, Gang Zhang, Wen Lu, Sicheng Zhang, Yi Yang, Ye BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling |
title | BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling |
title_full | BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling |
title_fullStr | BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling |
title_full_unstemmed | BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling |
title_short | BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling |
title_sort | btk suppresses myeloma cellular senescence through activating akt/p27/rb signaling |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593608/ https://www.ncbi.nlm.nih.gov/pubmed/28915637 http://dx.doi.org/10.18632/oncotarget.18096 |
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