Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in diffuse large B-cell lymphoma

Autor: 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
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Molecular Medicine, Vol 28, Iss 1, Pp 1-10 (2022)
Druh dokumentu: article
ISSN: 1076-1551
1528-3658
DOI: 10.1186/s10020-022-00518-0
Popis: 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.
Databáze: Directory of Open Access Journals
Externí odkaz: