Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma
Abstract 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 pl...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-022-00518-0 |
| _version_ | 1811320664366252032 |
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| author | Ji-Lin Chen Pei-Yi Chu Chun-Teng Huang Tzu-Ting Huang Wan-Lun Wang Yu-Hsuan Lee Yuan-Ya Chang Ming-Shen Dai Chung-Wai Shiau Chun-Yu Liu |
| author_facet | Ji-Lin Chen Pei-Yi Chu Chun-Teng Huang Tzu-Ting Huang Wan-Lun Wang Yu-Hsuan Lee Yuan-Ya Chang Ming-Shen Dai Chung-Wai Shiau Chun-Yu Liu |
| author_sort | Ji-Lin Chen |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T13:03:28Z |
| format | Article |
| id | doaj.art-d5ce200f0c8547a79007dd9f9fcc3b5d |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-04-13T13:03:28Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-d5ce200f0c8547a79007dd9f9fcc3b5d2022-12-22T02:45:51ZengBMCMolecular Medicine1076-15511528-36582022-08-0128111010.1186/s10020-022-00518-0Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphomaJi-Lin Chen0Pei-Yi Chu1Chun-Teng Huang2Tzu-Ting Huang3Wan-Lun Wang4Yu-Hsuan Lee5Yuan-Ya Chang6Ming-Shen Dai7Chung-Wai Shiau8Chun-Yu Liu9Comprehensive Breast Health Center, Taipei Veterans General HospitalDepartment of Pathology, Show Chwan Memorial HospitalSchool of Medicine, National Yang Ming Chiao Tung UniversityComprehensive Breast Health Center, Taipei Veterans General HospitalComprehensive Breast Health Center, Taipei Veterans General HospitalDivision of Medical Oncology, Department of Oncology, Taipei Veterans General HospitalDivision of Medical Oncology, Department of Oncology, Taipei Veterans General HospitalHematology/Oncology, Tri-Service General Hospital, National Defense Medical CenterInstitute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung UniversityComprehensive Breast Health Center, Taipei Veterans General HospitalAbstract 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.https://doi.org/10.1186/s10020-022-00518-0Diffuse large B cell lymphomaSHP-1Apoptosis |
| spellingShingle | Ji-Lin Chen Pei-Yi Chu Chun-Teng Huang Tzu-Ting Huang Wan-Lun Wang Yu-Hsuan Lee Yuan-Ya Chang Ming-Shen Dai Chung-Wai Shiau Chun-Yu Liu Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma Molecular Medicine Diffuse large B cell lymphoma SHP-1 Apoptosis |
| 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 | Diffuse large B cell lymphoma SHP-1 Apoptosis |
| url | https://doi.org/10.1186/s10020-022-00518-0 |
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