原调节蛋白 1 的沉默可通过提高核转运蛋白 α 2 介导的自噬来抑制急性髓性白血病细胞增殖和肿瘤生长。
Silencing of tropomodulin 1 inhibits acute myeloid leukemia cell proliferation and tumor growth by elevating karyopherin alpha 2-mediated autophagy.
发表日期：2024 Jul 28
作者：
Yuan Xia, Dan Wang, Huijie Zhao, Tingyi Meng, Qingling Jiang, Zhaohai Pan, Guoli Wang, Tianyue An, Bohan Li, Sixue Bi, Huikai Wang, Jun Lu, Hongfu Liu, Haiyan Lin, Chunhua Lin, Qiusheng Zheng, Defang Li
来源：
PHARMACOLOGICAL RESEARCH
摘要：
有证据表明，原调节蛋白 1 (TMOD1) 是多种癌症类型进展的强大诊断标志物。然而，TMOD1在肿瘤进展中的调控机制仍不清楚。在这里，我们发现 TMOD1 在急性髓系白血病 (AML) 标本中高表达，TMOD1 沉默通过诱导 AML THP-1 和 MOLM-13 细胞自噬来抑制细胞增殖。从机制上讲，TMOD1 的 C 端区域直接与 KPNA2 结合，TMOD1 过表达促进 KPNA2 泛素化并降低 KPNA2 水平。相反，TMOD1沉默增加了KPNA2水平并促进KPNA2的核转移，随后通过增加p53的核质运输和AMPK激活诱导自噬并抑制细胞增殖。 KPNA2/p53 抑制剂可减弱 AML 细胞中通过沉默 TMOD1 诱导的自噬。在携带 MOLM-13 异种移植物的裸鼠中，沉默 TMOD1 还可以通过增强 KPNA2 介导的自噬来抑制肿瘤生长。总的来说，我们的数据表明 TMOD1 可能成为 AML 治疗的新治疗靶点。版权所有 © 2024。由 Elsevier Ltd 出版。
Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.Copyright © 2024. Published by Elsevier Ltd.