CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism.
CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism.
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CDK7 抑制剂 THZ1 通过干扰细胞代谢诱导 B 细胞急性淋巴细胞白血病细胞凋亡
DOI：
10.3389/fonc.2021.663360
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发表时间：
2021
影响因子：
4.7
通讯作者：
Duan CW
中科院分区：
文献类型：
--
作者：
Abudureheman T;Xia J;Li MH;Zhou H;Zheng WW;Zhou N;Shi RY;Zhu JM;Yang LT;Chen L;Zheng L;Xue K;Qing K;Duan CW
B细胞急性淋巴细胞白血病（B-ALL）是一种恶性血液癌症，在儿童和成人中发展并导致高死亡率。THZ 1是一种共价的细胞周期蛋白依赖性激酶7（CDK 7）抑制剂，通过抑制细胞增殖和诱导细胞凋亡在各种癌症中显示出抗肿瘤作用。然而，THZ 1是否对B-ALL细胞具有抑制作用及其机制尚不清楚。在本研究中，我们发现THZ 1在低浓度下在体外阻滞B-ALL细胞的细胞周期，而在高浓度下通过激活凋亡途径诱导B-ALL细胞凋亡。此外，RNA-SEQ结果显示THZ 1扰乱了B-ALL细胞的细胞代谢途径。此外，THZ 1抑制B-ALL细胞的细胞代谢，并阻断细胞代谢中间产物的产生。THZ 1通过下调c-MYC介导的代谢酶的表达来抑制B-ALL的细胞代谢。然而，THZ 1处理增强过表达的c-MYC B-ALL细胞中的细胞凋亡，这与p53表达的上调有关。总的来说，我们的数据表明，CDK 7抑制剂THZ 1通过干扰c-MYC介导的细胞代谢诱导B-ALL细胞凋亡，从而为B-ALL提供了一种新的治疗选择。
B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.
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影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
8.8
作者：
Galbraith MD;Andrysik Z;Pandey A;Hoh M;Bonner EA;Hill AA;Sullivan KD;Espinosa JM
通讯作者：
Espinosa JM
影响因子：
16.6
作者：
Ghezzi, Chiara;Wong, Alicia;Clark, Peter M.
通讯作者：
Clark, Peter M.
影响因子：
16.6
作者：
Cayrol F;Praditsuktavorn P;Fernando TM;Kwiatkowski N;Marullo R;Calvo-Vidal MN;Phillip J;Pera B;Yang SN;Takpradit K;Roman L;Gaudiano M;Crescenzo R;Ruan J;Inghirami G;Zhang T;Cremaschi G;Gray NS;Cerchietti L
通讯作者：
Cerchietti L
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.