USP14是一种去泛素化酶，通过与蛋白酶体相互作用和去除靶蛋白的多泛素链而参与蛋白质降解。USP14可以影响细胞存活、DNA修复、内质网应激、内吞作用和炎症反应等细胞过程。USP14还在肿瘤生长中发挥作用，化合物IU1等抑制USP14可能影响癌细胞的迁移和侵袭。在本研究中，我们研究了IU1在ML1滤泡性甲状腺癌细胞中的作用机制，并将其与对照的原代甲状腺细胞进行了比较。IU1的处理以浓度依赖性的方式减少了ML1细胞的增殖，而且比对照细胞更为显著。IU1降低了ML1细胞的基础性迁移，并在刺激细胞使用生物活性化合物鞘氨醇1-磷酸酯后更为显著。与对照甲状腺细胞相比，鞘氨醇1-磷酸酯受体3在ML1细胞中增加，但这不受IU1的影响。进一步的机制研究表明，IU1增强了ML1细胞中的蛋白酶体活性以及LC3B依赖的自噬通量，而对对照甲状腺细胞产生了相反的效应。这表明IU1引发了与细胞类型相关的自噬反应，在ML1癌细胞中增加了自噬。IU1介导的自噬和蛋白酶体的刺激很可能有助于ML1细胞中观察到的细胞增殖和迁移的减少。在ML1甲状腺和其他癌细胞中，IU1影响的精确一套蛋白质应进一步研究。版权所有 © 2023 Srinivasan, Asghar, Zafar, Törnquist and Lindholm.

USP14 is a deubiquitinating enzyme involved in protein degradation by interacting with the proteasome and removal of poly-ubiquitin chains on target proteins. USP14 can influence cellular processes such as cell survival, DNA repair, ER stress, endocytosis, and the inflammatory response. USP14 further plays a role in tumor growth, and the inhibition of USP14 by compounds such as IU1 may affect cancer cell migration and invasion. Here we have studied the mechanisms for the action of IU1 in ML1 follicular thyroid cancer cells, comparing them with control, primary thyroid cells. Treatment with IU1 reduced proliferation of ML1 cells in a concentration-dependent manner, and more prominently than in control cells. IU1 decreased basal migration of ML1 cells, and after stimulation of cells with the bioactive compound, sphingosine-1-phosphate. The sphingosine-1-phosphate receptor 3 was increased in ML1 cells as compared with control thyroid cells, but this was not influenced by IU1. Further studies on the mechanism, revealed that IU1 enhanced the proteasome activity as well as LC3B-dependent autophagy flux in ML1 cells with an opposite effect on control thyroid cells. This indicates that IU1 elicits a cell-type dependent autophagy response, increasing it in ML1 cancer cells. The IU1-mediated stimulation of autophagy and proteasomes can likely contribute to the reduced cell proliferation and migration observed in ML1 cells. The precise set of proteins affected by IU1 in ML1 thyroid and other cancer cells warrant further investigations.Copyright © 2023 Srinivasan, Asghar, Zafar, Törnquist and Lindholm.