Targeted activation of GPER enhances the efficacy of venetoclax by boosting leukemic pyroptosis and CD8+T cell immune function in acute myeloid leukemia

作者全名:"Ren, Jun; Tao, Yonghong; Peng, Meixi; Xiao, Qiaoling; Jing, Yipei; Huang, Junpeng; Yang, Jing; Lin, Can; Sun, Minghui; Lei, Li; Yang, Zesong; Yang, Zailin; Zhang, Ling"

作者地址:"[Ren, Jun; Tao, Yonghong; Peng, Meixi; Xiao, Qiaoling; Jing, Yipei; Huang, Junpeng; Yang, Jing; Lin, Can; Sun, Minghui; Lei, Li; Zhang, Ling] Chongqing Med Univ, Sch Lab Med, Key Lab Lab Med Diagnost Designated Minist Educ, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Yang, Zesong] Chongqing Med Univ, Dept Hematol, Affiliated Hosp 1, Chongqing, Peoples R China; [Yang, Zailin] Chongqing Univ, Canc Hosp, Chongqing, Peoples R China"

通信作者:"Zhang, L (通讯作者),Chongqing Med Univ, Sch Lab Med, Key Lab Lab Med Diagnost Designated Minist Educ, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源:CELL DEATH & DISEASE

ESI学科分类:MOLECULAR BIOLOGY & GENETICS

WOS号:WOS:000877023400003

JCR分区:Q1

影响因子:9

年份:2022

卷号:13

期号:10

开始页: 

结束页: 

文献类型:Article

关键词: 

摘要:"Acute myeloid leukemia (AML) is a rapidly progressing and often fatal hematopoietic malignancy. Venetoclax (VEN), a recent FDA-approved BCL-2 selective inhibitor, has high initial response rates in elderly AML patients, but the majority of patients eventually acquire resistance. Multiple studies have demonstrated that the female sex is associated with better outcomes in patients with AML, which are predominantly attributed to estrogen signaling. As a novel membrane estrogen receptor, G protein-coupled estrogen receptor (GPER)-mediated-rapid estrogen effects have attracted considerable attention. However, whether targeting GPER enhances the antileukemic activity of VEN is unknown. In this study, we first demonstrated that GPER expression was dramatically reduced in AML cells owing to promoter hypermethylation. Furthermore, pharmacological activation of GPER by G-1 combined with VEN resulted in synergistic antileukemic activity in vitro and in vivo. Mechanistically, G-1/VEN combination synergistically triggered concurrent mitochondria-related apoptosis and gasdermin E (GSDME)-dependent pyroptosis by activating p38-MAPK/myeloid cell leukemia 1 (MCL-1) axis. Importantly, leukemic pyroptosis heightened CD8+ T cell immune function by releasing interleukin (IL)-1 beta/18 into the tumor microenvironment. Our study corroborates that GPER activation shows a synergistic antileukemic effect with VEN, making it a promising therapeutic regimen for AML."

基金机构:"National Natural Science Foundation of China [81873973, 82072353]; Natural Science Foundation of CQ CSTC [cstc2021jcyj-msxmX0363]; Graduate Scientific Research and Innovation Project of Chongqing [CYS20204]; Outstanding Postgraduate Fund of Chongqing Medical University [BJRC202210]"

基金资助正文:This work was supported by National Natural Science Foundation of China (Grant No: 81873973 and 82072353); Natural Science Foundation of CQ CSTC (Grant No: cstc2021jcyj-msxmX0363); Graduate Scientific Research and Innovation Project of Chongqing (Grant No: CYS20204); Outstanding Postgraduate Fund of Chongqing Medical University (Grant No: BJRC202210).