Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia.
Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia.
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靶向乳酸脱氢酶 A (LDHA) 对 T 细胞急性淋巴细胞白血病发挥抗白血病作用
DOI：
10.1002/cac2.12080
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Zhang G
中科院分区：
文献类型：
--
作者：
Yu H;Yin Y;Yi Y;Cheng Z;Kuang W;Li R;Zhong H;Cui Y;Yuan L;Gong F;Wang Z;Li H;Peng H;Zhang G
T细胞急性淋巴细胞白血病（T-ALL）是急性淋巴细胞白血病（ALL）的一种罕见和侵袭性亚型。在T-ALL患者的血清中，乳酸脱氢酶A（LDHA）的活性增加。我们提出，靶向LDHA可能是改善T-ALL结局的潜在策略。本研究旨在研究LDHA基因靶向治疗对T-ALL的抗白血病作用及其潜在的分子机制。原代T-ALL细胞系Jurkat和DU 528用LDH抑制剂草氨酸盐处理。进行MTT、集落形成、凋亡和细胞周期测定以研究草氨酸盐对T-ALL细胞的影响。应用定量真实的时间PCR（qPCR）和蛋白质印迹分析来确定相关信号通路。进行线粒体活性氧（ROS）测定以评价用草氨酸盐处理T-ALL细胞后的ROS产生。利用CRISPR/Cas9基因编辑技术建立LDHA基因敲低的T-ALL转基因斑马鱼模型，然后通过TUNEL、Western blotting和T-ALL肿瘤进展分析来研究LDHA基因敲低对T-ALL转基因斑马鱼的影响。Oxamate可明显抑制Jurkat和DU 528细胞的增殖并诱导其凋亡。细胞周期阻滞于G 0/G1期，并促进ROS的产生（P均< 0.001）。阻断LDHA显著降低了c-Myc的基因和蛋白表达，以及磷脂酰肌醇3′-激酶（PI 3 K）信号通路中磷酸化丝氨酸/苏氨酸激酶（AKT）和糖原合成酶激酶3 β（GSK-3β）的水平。在T-ALL转基因斑马鱼中，LDHA基因敲除延迟疾病进展并下调c-Myc mRNA和蛋白表达。靶向LDHA对T-ALL具有抗白血病作用，代表了T-ALL治疗的潜在策略。
T‐cell acute lymphoblastic leukemia (T‐ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T‐ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targeting LDHA may be a potential strategy to improve T‐ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene‐targeting treatment on T‐ALL and the underlying molecular mechanism. Primary T‐ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T‐ALL cells. Quantitative real‐time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluate ROS production after T‐ALL cells were treated with oxamate. A T‐ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene‐editing technology, and then TUNEL, Western blotting, and T‐ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T‐ALL transgenic zebrafish. Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P < 0.001). Blocking LDHA significantly decreased the gene and protein expression of c‐Myc, as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK‐3β) in the phosphatidylinositol 3′‐kinase (PI3K) signaling pathway. LDHA gene knockdown delayed disease progression and down‐regulated c‐Myc mRNA and protein expression in T‐ALL transgenic zebrafish. Targeting LDHA exerted an antileukemic effect on T‐ALL, representing a potential strategy for T‐ALL treatment.
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影响因子：
4.6
作者：
Dong T;Liu Z;Xuan Q;Wang Z;Ma W;Zhang Q
通讯作者：
Zhang Q
FOXM1 通过 LDHA 表达的反式激活促进瓦尔堡效应和胰腺癌进展。
DOI：
10.1158/1078-0432.ccr-13-2407
发表时间：
2014-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cui J;Shi M;Xie D;Wei D;Jia Z;Zheng S;Gao Y;Huang S;Xie K
通讯作者：
Xie K
影响因子：
9.7
作者：
Arseneault, Robert;Chien, Andrew;Cumming, Robert C.
通讯作者：
Cumming, Robert C.
影响因子：
29
作者：
Hu S;Balakrishnan A;Bok RA;Anderton B;Larson PE;Nelson SJ;Kurhanewicz J;Vigneron DB;Goga A
通讯作者：
Goga A
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.