Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin-proteasome pathway.

Abstract

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.

• Authors: Cunte Chen, Dingrui Nie, Youxue Huang, Xibao Yu, Zheng Chen, Mengjun Zhong, Xin Liu, Xianfeng Wang, Songnan Sui, Zhuandi Liu, Jiaxiong Tan, Zhi Yu, Yangqiu Li, Chengwu Zeng
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 112 Issue 4 Pg. 919-929 (10 2022) ISSN: 1938-3673 [Electronic] England
• PMID: 35363385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 Society for Leukocyte Biology.

Chemical References

• Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome
• Ubiquitins
• Proteasome Endopeptidase Complex
• Disulfiram

Topics

• Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome
• Disulfiram (pharmacology, therapeutic use)
• Humans
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Proteasome Endopeptidase Complex
• T-Lymphocytes
• Ubiquitins