Cytohesin-4/ARF6 facilitates the progression of acute myeloid leukemia through activating PIK3R5/PI3K/AKT pathway

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-05-12 DOI:10.1016/j.isci.2025.112634

Xiao-Fen Qiu (邱晓芬) , Cheng-Ming He (何程明) , Yan-Mei Zeng (曾艳梅) , Xiao-Ling Deng (邓晓玲) , Guo-Lin Liang (梁国林) , Ming-Xing Zhong (钟明星) , Min Zou (邹民) , Xiu-Juan Xiong (熊秀娟) , Jing-Dong Zhang (张敬东) , Yan Ye (叶燕) , Qing Niu (牛卿) , Xiao-Li Chen (陈晓梨)

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引用次数: 0

Abstract

In silico analysis revealed an elevated expression of cytohesin-4 (CYTH4) in acute myeloid leukemia (AML) cells, correlating with a poorer prognosis for AML patients. However, its role in AML is not fully understood. Our study using loss-of-function assays identified CYTH4 as an oncogene promoting leukemogenesis. Silencing CYTH4 in MV4-11 and THP-1 cells reduced cell proliferation and colony formation, and induced apoptosis and cell-cycle arrest at G0/G1, whereas overexpression had no significant impact. CYTH4 silencing also increased chemosensitivity to cytarabine. In a THP-1 xenograft model, CYTH4 silencing slowed AML progression and reduced leukemic cell homing and infiltration. Mechanistically, CYTH4 silencing inhibited PI3K/AKT pathway by lowering PIK3R5 and decreased ARF6-GTP levels, as confirmed by pull-down assays. Overexpression of PIK3R5 and AKT activation via SC-79 successfully countered the cellular dysfunctions from CYTH4 silencing. Thus, CYTH4 may play a role in AML progression, and targeting its pathway could be a promising anti-leukemic treatment strategy.

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细胞hesin-4/ARF6通过激活PIK3R5/PI3K/AKT通路促进急性髓系白血病的进展

计算机分析显示，在急性髓性白血病（AML）细胞中细胞增殖素-4 （CYTH4）的表达升高，与AML患者较差的预后相关。然而，其在AML中的作用尚不完全清楚。我们的研究使用功能缺失法鉴定出CYTH4是一种促进白血病发生的致癌基因。在MV4-11和THP-1细胞中沉默CYTH4可降低细胞增殖和集落形成，诱导细胞凋亡和细胞周期阻滞在G0/G1，而过表达CYTH4无显著影响。CYTH4沉默也增加了对阿糖胞苷的化学敏感性。在THP-1异种移植模型中，CYTH4沉默减缓了AML的进展，减少了白血病细胞的归巢和浸润。下拉实验证实，在机制上，CYTH4沉默通过降低PIK3R5和ARF6-GTP水平抑制PI3K/AKT通路。通过SC-79过表达PIK3R5和激活AKT成功对抗CYTH4沉默引起的细胞功能障碍。因此，CYTH4可能在AML进展中发挥作用，靶向其途径可能是一种有希望的抗白血病治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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