针对糖原合成酶激酶-3β的成人T细胞白血病治疗新策略

IF 2.3 3区 医学 Q2 HEMATOLOGY
Chie Ishikawa, Naoki Mori
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引用次数: 0

摘要

研究目的糖原合酶激酶(GSK)-3β在由人类T细胞白血病病毒1型(HTLV-1)引起的成人T细胞白血病(ATL)中的作用是矛盾和神秘的。在此,我们研究了 GSK-3β 的作用及其作为 ATL 治疗靶点的潜力:方法:分别使用 WST-8 试验、流式细胞术和 Hoechst 33342 染色法检测细胞增殖/存活、细胞周期、细胞凋亡和活性氧(ROS)生成。利用 RT-PCR、免疫荧光染色和免疫印迹分析了 GSK-3β 和细胞周期/死亡相关蛋白的表达以及存活信号:结果:HTLV-1感染的T细胞系出现了GSK-3β的核聚集。GSK-3β被敲除以及9-ING-41和LY2090314对其的抑制抑制了细胞的增殖/存活。9-ING-41 通过增强 γH2AX、p53、p21 和 p27 的表达,抑制 CDK1、细胞周期蛋白 A/B 和 c-Myc 的表达,诱导 G2/M 停滞。它通过降低 Bcl-xL、Mcl-1、XIAP、c-IAP1/2 和 survivin 的表达,以及增加 Bak 和 Bax 的表达,诱导 Caspase 介导的细胞凋亡。9-ING-41 还能诱导铁变态和坏死,促进 JNK 磷酸化,抑制 IKKγ 和 JunB 的表达。它抑制了 IκBα、Akt 和 STAT3/5 的磷酸化,诱导了 ROS 的产生,并降低了糖酵解衍生的乳酸水平:结论:GSK-3β在ATL中起着癌基因的作用,可能成为潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A New Strategy for Adult T-Cell Leukemia Treatment Targeting Glycogen Synthase Kinase-3β

Objectives

The role of glycogen synthase kinase (GSK)-3β in adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) is paradoxical and enigmatic. Here, we investigated the role of GSK-3β and its potential as a therapeutic target for ATL.

Methods

Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST-8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK-3β and cell cycle/death-related proteins, and survival signals was analyzed using RT-PCR, immunofluorescence staining, and immunoblotting.

Results

HTLV-1-infected T-cell lines showed nuclear accumulation of GSK-3β. GSK-3β knockdown and its inhibition with 9-ING-41 and LY2090314 suppressed cell proliferation/survival. 9-ING-41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c-Myc. It induced caspase-mediated apoptosis by decreasing the expression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9-ING-41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis-derived lactate levels.

Conclusion

GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target.

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来源期刊
CiteScore
5.50
自引率
0.00%
发文量
168
审稿时长
4-8 weeks
期刊介绍: European Journal of Haematology is an international journal for communication of basic and clinical research in haematology. The journal welcomes manuscripts on molecular, cellular and clinical research on diseases of the blood, vascular and lymphatic tissue, and on basic molecular and cellular research related to normal development and function of the blood, vascular and lymphatic tissue. The journal also welcomes reviews on clinical haematology and basic research, case reports, and clinical pictures.
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