靶向糖原合成酶激酶-3β的成人 T 细胞白血病治疗新策略。
A New Strategy for Adult T-Cell Leukemia Treatment Targeting Glycogen Synthase Kinase-3β.
机构信息
Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Japan.
出版信息
Eur J Haematol. 2024 Dec;113(6):852-862. doi: 10.1111/ejh.14300. Epub 2024 Sep 6.
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.
目的
糖原合酶激酶（GSK）-3β在人类 T 细胞白血病病毒 1（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。在这里，我们研究了 GSK-3β的作用及其作为 ATL 治疗靶点的潜力。
方法
使用 WST-8 测定法、流式细胞术和 Hoechst 33342 染色分别检测细胞增殖/存活、细胞周期、细胞凋亡和活性氧（ROS）生成。使用 RT-PCR、免疫荧光染色和免疫印迹分析 GSK-3β和细胞周期/死亡相关蛋白以及存活信号的表达。
结果
HTLV-1 感染的 T 细胞系显示 GSK-3β的核积累。GSK-3β 的敲低及其与 9-ING-41 和 LY2090314 的抑制抑制了细胞增殖/存活。9-ING-41 通过增强 γH2AX、p53、p21 和 p27 的表达，抑制 CDK1、cyclin A/B 和 c-Myc 的表达，诱导 G2/M 期阻滞。它通过降低 Bcl-xL、Mcl-1、XIAP、c-IAP1/2 和 survivin 的表达，增加 Bak 和 Bax 的表达，诱导 caspase 介导的细胞凋亡。9-ING-41 还诱导铁死亡和坏死性凋亡，促进 JNK 磷酸化，抑制 IKKγ 和 JunB 的表达。它抑制 IκBα、Akt 和 STAT3/5 的磷酸化，诱导 ROS 生成，并降低糖酵解衍生的乳酸水平。
结论
GSK-3β在 ATL 中作为癌基因发挥作用，可能是一个潜在的治疗靶点。
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