Theranostics 2022; 12(12):5537-5550. doi:10.7150/thno.72786 This issue

Research Paper

Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression

Na Ning1, Si Zhang2, Qi Wu3, Xun Li1, Dong Kuang4,5, Yaqi Duan4,5, Minghui Xia1, Huicheng Liu1, Junmei Weng1, Hongping Ba1, Zhaohui Tang6, Xiang Cheng2, Heng Mei7, Liu Huang8, Qilin Ao4,5, Guoping Wang4,5, Yu Hu7, Arian Laurence9, Jing Wang1*, Guihua Wang3*, Xiang-Ping Yang1*✉

1. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
2. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, HUST, Wuhan, China
3. GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, HUST, Wuhan, China
4. Institute of Pathology, Tongji Hospital, Tongji Medical College, HUST, Wuhan, China
5. Department of Pathology, School of Basic Medicine, Tongji Medical College, HUST, Wuhan, China
6. Department of Surgery, Tongji Hospital, Tongji Medical College, HUST, Wuhan, China
7. Institute of Hematology, Union Hospital, Tongji Medical College, HUST, Wuhan, China
8. Department of Oncology, Tongji Hospital, Tongji Medical College, HUST, Wuhan, China
9. Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom
*Those senior authors contributed equally

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Ning N, Zhang S, Wu Q, Li X, Kuang D, Duan Y, Xia M, Liu H, Weng J, Ba H, Tang Z, Cheng X, Mei H, Huang L, Ao Q, Wang G, Hu Y, Laurence A, Wang J, Wang G, Yang XP. Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression. Theranostics 2022; 12(12):5537-5550. doi:10.7150/thno.72786. Available from https://www.thno.org/v12p5537.htm

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Abstract

Graphic abstract

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.

Keywords: DLBCL, Venetoclax, AGK, BCL-2, FOXO1