Secreted insulin-like growth factor binding protein 5 functions as a tumor suppressor and chemosensitizer through inhibiting insulin-like growth factor 1 receptor/protein kinase B pathway in acute myeloid leukemia.
Secreted insulin-like growth factor binding protein 5 functions as a tumor suppressor and chemosensitizer through inhibiting insulin-like growth factor 1 receptor/protein kinase B pathway in acute myeloid leukemia.
复制标题
DOI：
10.1016/j.neo.2023.100952
复制
发表时间：
2024-01
期刊：
影响因子：
4.8
通讯作者：
Chen, Xiaoli
中科院分区：
文献类型：
--
作者：
Zhang, Beiying;Deng, Xiaoling;You, Ruolan;Liu, Jingru;Hou, Diyu;Wang, Xiaoting;Chen, Shucheng;Li, Dongliang;Fu, Qiang;Zhang, Jingdong;Huang, Huifang;Chen, Xiaoli
除了通过胞吐作用分泌到细胞间隙中之外，胰岛素样生长因子结合蛋白5（IGFBP 5）也可以保留在胞质溶胶中或被转运到细胞核。根据不同的细胞环境和亚细胞分布，IGFBP 5可以通过胰岛素样生长因子依赖性或非依赖性机制作为肿瘤抑制剂或促进剂。然而，关于IGFBP 5对急性髓系白血病（AML）的影响及其潜在机制知之甚少。本研究利用重组人IGFBP 5（rhIGFBP 5）蛋白和异位稳定表达IGFBP 5或缺失分泌信号肽的突变型IGFBP 5（mtIGFBP 5）的U937和THP 1细胞系，研究IGFBP 5在人AML中的作用。采用流式细胞仪和细胞计数试剂盒检测细胞活力、细胞凋亡和细胞周期分布。细胞毒试验检测化疗药物敏感性。采用白血病异种移植模型和苏木精-伊红染色评价体内AML进展和髓外浸润。计算机模拟分析表明IGFBP 5表达与AML患者的总生存率呈正相关。IGFBP 5过表达和外源性rhIGFBP 5均能诱导THP 1和U937细胞凋亡，阻滞G1/S期转换，从而抑制细胞生长，并能提高U937和THP 1细胞对柔红霉素和阿糖胞苷的化疗敏感性。然而，mtIGFBP 5的过表达未能证明这些特性。U937细胞的体内异种移植小鼠模型也表明IGFBP 5而不是mtIGFBP 5的过表达减轻了AML进展和髓外浸润。从机制上讲，这些生物学后果取决于胰岛素样生长因子1受体介导的磷脂酰肌醇-3-激酶/蛋白激酶B途径的失活。我们的研究结果显示分泌型而不是细胞内IGFBP 5作为AML的肿瘤抑制剂和化疗增敏剂。通过过量表达或添加外源性rhIGFBP 5上调血清IGFBP 5可能作为AML的合适治疗方法。
In addition to being secreted into the intercellular spaces by exocytosis, insulin-like growth factor binding protein 5 (IGFBP5) may also remain in the cytosol or be transported to the nucleus. Depending on the different cellular context and subcellular distribution, IGFBP5 can act as a tumor suppressor or promoter through insulin-like growth factor -dependent or -independent mechanisms. Yet, little is known about the impacts of IGFBP5 on acute myeloid leukemia (AML) and its underlying mechanism. Here we investigated the roles of IGFBP5 in human AML by using recombinant human IGFBP5 (rhIGFBP5) protein and U937 and THP1 cell lines which stably and ectopically expressed IGFBP5 or mutant IGFBP5 (mtIGFBP5) with the lack of secretory signal peptide. Cell counting kit-8 and flow cytometry assay were conducted to assess the cell viability, cell apoptosis and cell cycle distribution. Cytotoxicity assay was used to detect the chemosensitivity. Leukemia xenograft model and hematoxylin-eosin staining were performed to evaluate AML progression and extramedullary infiltration in vivo. In silico analysis demonstrated a positive association between IGFBP5 expression and overall survival of the AML patients. Both IGFBP5 overexpression and extrinsic rhIGFBP5 suppressed the growth of THP1 and U937 cells by inducing cell apoptosis and arresting G1/S transition and promoted the chemosensitivity of U937 and THP1 cells to daunorubicin and cytarabine. However, overexpression of mtIGFBP5 failed to demonstrate these properties. An in vivo xenograft mouse model of U937 cells also indicated that overexpression of IGFBP5 rather than mtIGFBP5 alleviated AML progression and extramedullary infiltration. Mechanistically, these biological consequences depended on the inactivation of insulin-like growth factor 1 receptor -mediated phosphatidylinositol-3-kinase/protein kinase B pathway. Our findings revealed secreted rather than intracellular IGFBP5 as a tumor-suppressor and chemosensitizer in AML. Upregulation of serum IGFBP5 by overexpression or addition of extrinsic rhIGFBP5 may serve as a suitable therapeutic approach for AML.
登录
查看更多内容
IGFBP5 的过度表达通过 PI3K-AKT 途径增强前列腺癌的放射敏感性
影响因子：
3.3
作者：
Chen, Xue;Yu, Qi;Fu, Shen
通讯作者：
Fu, Shen
影响因子：
6
作者：
Pilewski, JM;Liu, LX;Feghali-Bostwick, CA
通讯作者：
Feghali-Bostwick, CA
影响因子：
3.8
作者：
Akkiprik M;Hu L;Sahin A;Hao X;Zhang W
通讯作者：
Zhang W
影响因子：
2.3
作者：
通讯作者：
--
影响因子：
28.5
作者：
Chen X;Zheng J;Zou Y;Song C;Hu X;Zhang CC
通讯作者：
Zhang CC