TCFL5 敲低通过调节 GPX4 使弥漫性大 B 细胞淋巴瘤对阿霉素治疗敏感。
TCFL5 knockdown sensitizes DLBCL to doxorubicin treatment via regulation of GPX4.
机构信息
Graduate School, Nanjing Medical University, Nanjing 210000, China.
Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian 223300, China.
出版信息
Cell Signal. 2023 Oct;110:110831. doi: 10.1016/j.cellsig.2023.110831. Epub 2023 Jul 27.
BACKGROUND
Resistance to chemo-drug is a major cause of bad outcome in diffuse large B-cell lymphoma (DLBCL). It was reported that TCFL5 may be related to chemoresistance in childhood acute lymphoblastic leukemia. However, it is still unclear whether TCFL5 is involved in DLBCL drug-resistance.
METHODS
To explore the underlying mechanism of doxorubicin resistance, recombinant lentivirus was applied to control expression of TCFL5 in DLBCL cells. CCK-8 assay was perfomed to investigate the influence of doxorubicin on proliferation of TCFL5-overexpressed or sh-TCFL5 DLBCL cells. Correlation between TCFL5 and GPX4 was analyzed with bioinformatic methods, which was further confirmed by qPCR and western blot. TCFL5 overexpression conferred doxorubicin resistance via regulating GPX4 and was verified by TUNEL assay and western blot in vitro and mice model in vivo.
RESULTS
TCFL5 was enriched in DLBCL cells and conferred doxorubicin resistance through binding to GPX4. Inhibition of TCFL5 enhanced the sensitivity of DLBCL cells to doxorubicin. GPX4 knockdown reversed doxorubicin resistance in TCFL5-overexpressed DLBCL cells.
CONCLUSION
DLBCL cells overexpress TCFL5 that promotes chemoresistance by regulating GPX4. Targeting TCFL5 may provide a prospective therapeutic strategy for doxorubicin-resistant DLBCL.
背景
化疗耐药是弥漫性大 B 细胞淋巴瘤（DLBCL）不良预后的主要原因。有报道称，TCFL5 可能与儿童急性淋巴细胞白血病的化疗耐药有关。然而，TCFL5 是否参与 DLBCL 耐药尚不清楚。
方法
为了探讨多柔比星耐药的潜在机制，应用重组慢病毒控制 DLBCL 细胞中 TCFL5 的表达。CCK-8 法检测 TCFL5 过表达或 sh-TCFL5 DLBCL 细胞中多柔比星对增殖的影响。采用生物信息学方法分析 TCFL5 与 GPX4 的相关性，并通过 qPCR 和 Western blot 进一步验证。TCFL5 过表达通过调节 GPX4 赋予多柔比星耐药性，并通过体外 TUNEL 检测和 Western blot 以及体内小鼠模型进行验证。
结果
TCFL5 在 DLBCL 细胞中富集，并通过与 GPX4 结合赋予多柔比星耐药性。抑制 TCFL5 增强了 DLBCL 细胞对多柔比星的敏感性。TCFL5 过表达的 DLBCL 细胞中 GPX4 敲低逆转了多柔比星耐药性。
结论
DLBCL 细胞过表达 TCFL5，通过调节 GPX4 促进化疗耐药。靶向 TCFL5 可能为多柔比星耐药的 DLBCL 提供有前景的治疗策略。
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