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Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance
Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741995/ https://www.ncbi.nlm.nih.gov/pubmed/26517678 |
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author | Kim, Areumnuri Seong, Ki Moon Kang, Hye Jin Park, Sunhoo Lee, Seung-Sook |
author_facet | Kim, Areumnuri Seong, Ki Moon Kang, Hye Jin Park, Sunhoo Lee, Seung-Sook |
author_sort | Kim, Areumnuri |
collection | PubMed |
description | Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resistant MCL cells in vitro and in vivo. We demonstrate that BTZ-resistant MCL cells showed highly increased expression of the B-cell receptor (BCR) components CD79A and CD19. Activation of the BCR signaling pathway enhanced the activity of Src family kinases (SFKs), especially Lyn, and downstream kinases PI3K/AKT/mTOR in BTZ-resistant MCL cells. Depletion of CD79A and Lyn significantly reduced several kinase activities involved in PI3K signaling, leading to inhibition of proliferation. In addition, the SFKs inhibitor dasatinib inhibited the proliferation of BTZ-resistant cells, preventing the binding of CD19 with Lyn and PI3K p85. We also verified our findings with the mouse xenograft tumor model. Dasatinib treatment significantly decreased tumor size in the mouse bearing BTZ-resistant MCL cells, but not in the mouse bearing BTZ-sensitive MCL cells. Collectively, our data show that overexpression of the BCR and its activated signaling confers BTZ resistance in MCL cells. Thus, targeting BCR signaling with dasatinib could be a novel therapeutic approach for patients with MCL that has relapsed or is refractory to treatment with BTZ. |
format | Online Article Text |
id | pubmed-4741995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-47419952016-03-17 Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance Kim, Areumnuri Seong, Ki Moon Kang, Hye Jin Park, Sunhoo Lee, Seung-Sook Oncotarget Research Paper Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resistant MCL cells in vitro and in vivo. We demonstrate that BTZ-resistant MCL cells showed highly increased expression of the B-cell receptor (BCR) components CD79A and CD19. Activation of the BCR signaling pathway enhanced the activity of Src family kinases (SFKs), especially Lyn, and downstream kinases PI3K/AKT/mTOR in BTZ-resistant MCL cells. Depletion of CD79A and Lyn significantly reduced several kinase activities involved in PI3K signaling, leading to inhibition of proliferation. In addition, the SFKs inhibitor dasatinib inhibited the proliferation of BTZ-resistant cells, preventing the binding of CD19 with Lyn and PI3K p85. We also verified our findings with the mouse xenograft tumor model. Dasatinib treatment significantly decreased tumor size in the mouse bearing BTZ-resistant MCL cells, but not in the mouse bearing BTZ-sensitive MCL cells. Collectively, our data show that overexpression of the BCR and its activated signaling confers BTZ resistance in MCL cells. Thus, targeting BCR signaling with dasatinib could be a novel therapeutic approach for patients with MCL that has relapsed or is refractory to treatment with BTZ. Impact Journals LLC 2015-10-21 /pmc/articles/PMC4741995/ /pubmed/26517678 Text en Copyright: © 2015 Kim et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Kim, Areumnuri Seong, Ki Moon Kang, Hye Jin Park, Sunhoo Lee, Seung-Sook Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
title | Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
title_full | Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
title_fullStr | Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
title_full_unstemmed | Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
title_short | Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
title_sort | inhibition of lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741995/ https://www.ncbi.nlm.nih.gov/pubmed/26517678 |
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