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Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma
BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive and molecularly heterogeneous non-Hodgkin’s lymphoma. The B cell receptor (BCR) signaling pathway in DLBCL emerges as a new drug target. Protein phosphatase SHP-1 negatively regulates several oncogenic tyrosine kinases and plays a tu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9358803/ https://www.ncbi.nlm.nih.gov/pubmed/35941532 http://dx.doi.org/10.1186/s10020-022-00518-0 |
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author | Chen, Ji-Lin Chu, Pei-Yi Huang, Chun-Teng Huang, Tzu-Ting Wang, Wan-Lun Lee, Yu-Hsuan Chang, Yuan-Ya Dai, Ming-Shen Shiau, Chung-Wai Liu, Chun-Yu |
author_facet | Chen, Ji-Lin Chu, Pei-Yi Huang, Chun-Teng Huang, Tzu-Ting Wang, Wan-Lun Lee, Yu-Hsuan Chang, Yuan-Ya Dai, Ming-Shen Shiau, Chung-Wai Liu, Chun-Yu |
author_sort | Chen, Ji-Lin |
collection | PubMed |
description | BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive and molecularly heterogeneous non-Hodgkin’s lymphoma. The B cell receptor (BCR) signaling pathway in DLBCL emerges as a new drug target. Protein phosphatase SHP-1 negatively regulates several oncogenic tyrosine kinases and plays a tumor suppressive role. METHODS: The direct SHP-1 agonists were used to evaluate the potential therapeutic implication of SHP-1 in DLBCL. Immunohistochemical staining for SHP-1 was quantified by H-score. The SHP-1 phosphatase activity was determined using tyrosine phosphatase assay. In vitro studies, including MTT, western blot analysis and cell apoptosis, were utilized to examined biological functions of SHP-1. RESULTS: Oral administration of SHP-1 agonist showed the potent anti-tumor effects compared to a selective Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib in mice bearing U2932 xenografts. SHP-1 agonist increased SHP-1 activity as well as downregulated p-Lyn in vivo. Here, we demonstrated that immunohistochemical staining for SHP-1 expression was positive in 76% of DLBCL samples. SHP-1 agonist exerted anti-proliferative and apoptotic effects compared with ibrutinib in DLBCL cells. Mechanistically, SHP-1 agonist decreased BCR signaling, especially p-Lyn, and led to apoptosis. CONCLUSIONS: These data suggest that SHP-1 negatively regulates phosphorylation of Lyn, and targeting SHP-1/p-Lyn using SHP-1 agonist has therapeutic potential for treatment of DLBCL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-022-00518-0. |
format | Online Article Text |
id | pubmed-9358803 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-93588032022-08-10 Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma Chen, Ji-Lin Chu, Pei-Yi Huang, Chun-Teng Huang, Tzu-Ting Wang, Wan-Lun Lee, Yu-Hsuan Chang, Yuan-Ya Dai, Ming-Shen Shiau, Chung-Wai Liu, Chun-Yu Mol Med Research Article BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is an aggressive and molecularly heterogeneous non-Hodgkin’s lymphoma. The B cell receptor (BCR) signaling pathway in DLBCL emerges as a new drug target. Protein phosphatase SHP-1 negatively regulates several oncogenic tyrosine kinases and plays a tumor suppressive role. METHODS: The direct SHP-1 agonists were used to evaluate the potential therapeutic implication of SHP-1 in DLBCL. Immunohistochemical staining for SHP-1 was quantified by H-score. The SHP-1 phosphatase activity was determined using tyrosine phosphatase assay. In vitro studies, including MTT, western blot analysis and cell apoptosis, were utilized to examined biological functions of SHP-1. RESULTS: Oral administration of SHP-1 agonist showed the potent anti-tumor effects compared to a selective Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib in mice bearing U2932 xenografts. SHP-1 agonist increased SHP-1 activity as well as downregulated p-Lyn in vivo. Here, we demonstrated that immunohistochemical staining for SHP-1 expression was positive in 76% of DLBCL samples. SHP-1 agonist exerted anti-proliferative and apoptotic effects compared with ibrutinib in DLBCL cells. Mechanistically, SHP-1 agonist decreased BCR signaling, especially p-Lyn, and led to apoptosis. CONCLUSIONS: These data suggest that SHP-1 negatively regulates phosphorylation of Lyn, and targeting SHP-1/p-Lyn using SHP-1 agonist has therapeutic potential for treatment of DLBCL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-022-00518-0. BioMed Central 2022-08-08 /pmc/articles/PMC9358803/ /pubmed/35941532 http://dx.doi.org/10.1186/s10020-022-00518-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Chen, Ji-Lin Chu, Pei-Yi Huang, Chun-Teng Huang, Tzu-Ting Wang, Wan-Lun Lee, Yu-Hsuan Chang, Yuan-Ya Dai, Ming-Shen Shiau, Chung-Wai Liu, Chun-Yu Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma |
title | Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma |
title_full | Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma |
title_fullStr | Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma |
title_full_unstemmed | Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma |
title_short | Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma |
title_sort | interfering b cell receptor signaling via shp-1/p-lyn axis shows therapeutic potential in diffuse large b-cell lymphoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9358803/ https://www.ncbi.nlm.nih.gov/pubmed/35941532 http://dx.doi.org/10.1186/s10020-022-00518-0 |
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