Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression.
Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression.
复制标题
抑制酰基甘油激酶通过上调 FOXO1 介导的 BCL-2 表达使 DLBCL 对 Venetoclax 敏感
DOI：
10.7150/thno.72786
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Yang, Xiang-Ping
中科院分区：
文献类型：
--
作者：
Ning, Na;Zhang, Si;Wu, Qi;Li, Xun;Kuang, Dong;Duan, Yaqi;Xia, Minghui;Liu, Huicheng;Weng, Junmei;Ba, Hongping;Tang, Zhaohui;Cheng, Xiang;Mei, Heng;Huang, Liu;Ao, Qilin;Wang, Guoping;Hu, Yu;Laurence, Arian;Wang, Jing;Wang, Guihua;Yang, Xiang-Ping
背景资料：尽管维奈托克治疗急性髓性白血病（AML）和慢性淋巴细胞白血病（CLL）的范式发生了变化，但在治疗弥漫性大B细胞淋巴瘤（DLBCL）方面却不太成功。在这里，我们探讨了酰基甘油激酶是否调节DLBCL对维奈托克的敏感性及其在细胞系和临床前动物模型中的机制。方法：检测7株DLBCL细胞系AGK的表达及对维奈托克的敏感性。在DLBCL细胞中通过慢病毒敲低和过表达AGK后，在体外评价了维奈托克诱导的细胞凋亡和PTEN-FOXO 1-BCL-2信号轴。在植入对照或shAGK稳定转导的SU-DHL 4细胞的免疫缺陷NCG小鼠中评价维奈托克和PTEN-FOXO 1-BCL-2信号传导轴的功效。检测DLBCL患者肿瘤组织中AGK、BCL-2和FOXO 1的表达。结果：AGK表达与DLBCL对维奈托克的敏感性呈负相关。抑制AGK使DLBCL细胞对维奈托克更敏感。从机制上讲，AGK磷酸化和失活PTEN，导致AKT激活和减少FOXO 1核转位。AGK的抑制还导致维奈托克在体内抑制DLBCL肿瘤生长的功效增强，这依赖于FOXO 1。在人DLBCL肿瘤组织中，AGK的表达与BCL-2的表达以及核FOXO 1的量呈负相关。结论：AGK通过PTEN-FOXO 1-BCL-2信号通路调节DLBCL对维奈托克的反应。靶向AGK可增强维奈托克治疗DLBCL患者的疗效。
Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro. The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.
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DOI：
10.1084/jem.20161263
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Inoue T;Shinnakasu R;Ise W;Kawai C;Egawa T;Kurosaki T
通讯作者：
Kurosaki T
一种产生溶血磷脂酸的新型酰基甘油激酶可调节前列腺癌细胞中与 EGFR 的串扰。
DOI：
10.1083/jcb.200407123
发表时间：
2005-06-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bektas M;Payne SG;Liu H;Goparaju S;Milstien S;Spiegel S
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Spiegel S
影响因子：
9
作者：
Kapoor I;Bodo J;Hill BT;Hsi ED;Almasan A
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Almasan A
影响因子：
45.3
作者：
Herrera, Alex F.;Mei, Matthew;Armand, Philippe
通讯作者：
Armand, Philippe
影响因子：
5.5
作者：
Chu B;Hong Z;Zheng X
通讯作者：
Zheng X