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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...

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Autores principales: Gu, Chunyan, Peng, Hailin, Lu, Yue, Yang, Hongbao, Tian, Zhidan, Yin, Gang, Zhang, Wen, Lu, Sicheng, Zhang, Yi, Yang, Ye
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
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.
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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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