CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism.
CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism.
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CDK9 抑制剂通过抑制 c-Myc 介导的糖酵解代谢诱导 B 细胞急性淋巴细胞白血病凋亡
DOI：
10.3389/fcell.2021.641271
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发表时间：
2021
影响因子：
5.5
通讯作者：
Duan CW
中科院分区：
文献类型：
--
作者：
Huang WL;Abudureheman T;Xia J;Chu L;Zhou H;Zheng WW;Zhou N;Shi RY;Li MH;Zhu JM;Qing K;Ji C;Liang KW;Guo S;Yin G;Duan CW
B细胞急性淋巴细胞白血病（B-ALL）是一种常见的儿童血液肿瘤，导致高死亡率。细胞周期蛋白依赖性激酶9抑制剂（CDK 9 i）通过诱导细胞凋亡和抑制细胞增殖有效地减轻急性髓细胞白血病和慢性淋巴细胞白血病。然而，CDK 9 i对B-ALL细胞的作用及其机制尚不清楚。在这项研究中，我们发现CDK 9 i通过激活凋亡途径在体外诱导B-ALL细胞凋亡。此外，CDK 9 i抑制B-ALL细胞的糖酵解代谢，与糖酵解抑制剂共同处理可增强CDK 9 i诱导的凋亡。此外，CDK 9 i通过显著下调葡萄糖转运蛋白1（GLUT 1）和糖酵解关键限速酶（如己糖激酶2（HK 2）和乳酸脱氢酶A（LDHA））的表达来抑制B-ALL细胞系的糖酵解。此外，在用CDK 9 i处理后，具有过表达c-Myc的B-ALL细胞中的细胞凋亡被拯救，这参与了糖酵解代谢的增强。综上所述，我们的研究结果表明，CDK 9抑制剂通过抑制c-Myc介导的糖酵解代谢诱导B-ALL细胞凋亡，从而为B-ALL的治疗提供了新的策略。
B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.
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影响因子：
7.3
作者：
Sonawane YA;Taylor MA;Napoleon JV;Rana S;Contreras JI;Natarajan A
通讯作者：
Natarajan A
影响因子：
11.5
作者：
Cidado, Justin;Boiko, Scott;Drew, Lisa
通讯作者：
Drew, Lisa
影响因子：
4
作者：
Carolina Franco, Lia;Morales, Fatima;Giordano, Antonio
通讯作者：
Giordano, Antonio
影响因子：
9.3
作者：
Abdel-Wahab, Ali F.;Mahmoud, Waheed;Al-Harizy, Randa M.
通讯作者：
Al-Harizy, Randa M.
影响因子：
4.8
作者：
Itkonen, Harri M.;Poulose, Ninu;Mills, Ian G.
通讯作者：
Mills, Ian G.