Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin-proteasome pathway
Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin-proteasome pathway
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DOI：
10.1002/jlb.5ma1121-644r
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发表时间：
2022-04-01
影响因子：
5.5
通讯作者：
Zeng, Chengwu
中科院分区：
文献类型：
--
作者：
Chen, Cunte;Nie, Dingrui;Zeng, Chengwu
T细胞恶性肿瘤，包括T细胞急性淋巴细胞白血病（T-ALL）和T细胞淋巴瘤（TCL），具有治疗效果差、异质性高、预后差、缺乏特异性治疗靶点和改善预后的药物等特点。双硫仑 (DSF) 是一种临床上用于控制酗酒的药物，最近被证明对多种癌症具有细胞毒性。然而，DFS 治疗 T 细胞恶性肿瘤患者的潜在作用和机制尚不清楚。在这项研究中，我们报道 DSF 促进细胞凋亡并抑制恶性 T 细胞系和原代 T-ALL 细胞的增殖。我们提供的证据表明，DSF 通过靶向 NPL4 介导的泛素蛋白酶体途径，在 T 细胞恶性肿瘤中发挥抗癌活性。值得注意的是，NPL4 和 2 个泛素蛋白酶体通路基因、后期促进复合物亚基 1 (ANAPC1) 和蛋白酶体 26S 亚基泛素受体、非 ATP 酶 2 (PSMD2) 的高表达与 TCL 和 T-ALL 患者不利的总生存 (OS) 显着相关 (p < 0.05)。更重要的是，NPL4、ANAPC1和PSMD2的加权组合可以在列线图模型中直观地显示T细胞恶性肿瘤患者的1年、3年和5年OS率，并促进风险分层。具体而言，风险分层是 T 细胞恶性肿瘤患者 OS 的独立预测因子。总之，DSF可能通过NPL4介导的泛素蛋白酶体途径诱导恶性T细胞凋亡并抑制其增殖，为T细胞恶性肿瘤提供潜在的治疗选择。
T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T-cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T-cell cell lines and primary T-ALL cells. We provide evidence that DSF exerts anticancer activity in T-cell malignancies by targeting the NPL4-mediated ubiquitin-proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin-proteasome pathway genes, anaphase-promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T-ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1-, 3-, and 5-year OS rates for patients with T-cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T-cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T-cells via the NPL4-mediated ubiquitin-proteasome pathway and offer a potential therapeutic option for T-cell malignancies.