吴茱萸碱调节Shh/Gli1信号通路对弥漫性大B细胞淋巴瘤细胞利妥昔单抗耐药性的影响

doi:10.3969/j.issn.1006-6233.2024.04.02

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Abstract Objective: To investigate the impacts of evodiamine on rituximab (RIT) resistance in diffuse large B-cell lymphoma (DLBCL) cells by regulating the Shh/Gli family zinc finger protein 1 (Gli1) signal pathway. Methods: OCI-LY10 cells were cultured in vitro and their RIT resistant cell line OCI-LY10/RIT was constructed using gradient drug addition method. All cells were treated with 0, 1, 5, 10, 20 and 30 μmoL/L of evodiamine, CCK-8 method was applied to determine the activity of OCI-LY10 and OCI-LY10/RIT cells in each group and to screen the optimal concentration of evodiamine. OCI-LY10/RIT cells were randomly grouped into control group, RIT group, RIT+evodiamine group, RIT+empty group, and RIT+evodiamine+Shh overexpression group, after grouping and processing, real-time fluorescence quantitative PCR and immunoblotting experiments were applied to detect the expression of Shh/Gli1 pathway related mRNA and protein of cells in each group; CCK-8 method and Edu staining were applied to detect cell proliferation in each group; flow cytometry was applied to detect cell apoptosis in each group; Western blot was applied to detect the expression of apoptotic proteins (Cleaved Caspase-3, Bax) and drug resistance proteins [multiple drug resistance related protein 5 (MRP5), P-glycoprotein (P-gp)] in each group. OCI-LY10/RIT cells were cultured in vitro and randomly grouped into a control group, a evodiamine group, an empty group, and a evodiamine+Shh overexpression group, after grouping and processing, the CCK-8 method was applied to detect the survival rate of OCI-LY10/RIT cells in each group under 0, 16, 32, 64, 128, 256 and 384 μg/mL RIT treatment, and calculate their drug resistance index. Results: Compared with the control group, the apoptosis rate, the expression of Cleaved Caspase-3 and Bax proteins in the RIT+evodiamine group increased (P<0.05), the expression of Shh, Gli1 mRNAs and proteins, survival rate, Edu positive rate, and the expression of MRP5 and P-gp proteins decreased (P<0.05); there was no obvious change in all cell indicators in the RIT group and the RIT+empty group (P>0.05). Compared with the RIT group, the apoptosis rate, the expression of Cleaved Caspase-3 and Bax proteins in the RIT group and the RIT+empty group increased (P<0.05), the expression of Shh, Gli1 mRNAs and proteins, survival rate, Edu positive rate, and the expression of MRP5 and P-gp proteins decreased (P<0.05); there was no obvious change in all indicators of cells in the RIT+empty group (P>0.05). Compared with the RIT+evodiamine group, the apoptosis rate, the expression of Cleaved Caspase-3 and Bax proteins in the RIT+evodiamine+Shh overexpression group decreased (P<0.05), the expression of Shh, Gli1 mRNAs and proteins, survival rate, Edu positive rate, and the expression of MRP5 and P-gp proteins increased (P<0.05). Compared with the control group, the cell resistance index in the evodiamine group decreased (P<0.05), the drug resistance index of cells in the empty group showed no obvious change (P>0.05); compared with the Evodiamine group, the evodiamine+Shh overexpression group showed an increase in cell resistance index (P<0.05). Conclusion: Evodiamine can down-regulate the expression of Shh/Gli1 pathway related proteins, thereby reducing RIT resistance in DLBCL cells, inducing apoptosis and inhibiting proliferation of RIT resistant DLBCL cells under RIT treatment.

Key words： Diffuse large B-cell lymphoma Evodiamine Shh/Gli1 Rituximab Resistance

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http://www.hbyxzzs.cn/EN/10.3969/j.issn.1006-6233.2024.04.02 OR http://www.hbyxzzs.cn/EN/Y2024/V30/I4/536

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