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The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity

文献类型：期刊论文

作者Xuan, Yi-Fei1,2; Lu, Shan1,2; Ou, Ying-Jie1,2; Bao, Xu-Bin2; Huan, Xia-Juan2; Song, Shan-Shan2; Miao, Ze-Hong1,2; Wang, Ying-Qing1,2
刊名BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
出版日期2024-07-05
卷号716页码:12
关键词MAT2A inhibitor METTL3 inhibitor m6A Combination therapy NSCLC
ISSN号0006-291X
DOI10.1016/j.bbrc.2024.150011
通讯作者Miao, Ze-Hong(zhmiao@simm.ac.cn) ; Wang, Ying-Qing(yqwang@simm.ac.cn)
英文摘要Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S -Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase ( MTAP ) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m 6 A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non -small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve antitumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG -270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti -tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m 6 A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo . In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro , which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.
WOS关键词MESSENGER-RNA ; GROWTH ; METTL3
资助项目National Natural Science Foundation of China[82073865] ; National Natural Science Foundation of China[81773764] ; Science and Technology Commission of Shanghai Municipality[20ZR1468100] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231010] ; State Key Laboratory of Drug Research
WOS研究方向Biochemistry & Molecular Biology ; Biophysics
语种英语
WOS记录号WOS:001239644300001
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/311609]  
专题新药研究国家重点实验室
通讯作者Miao, Ze-Hong; Wang, Ying-Qing
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xuan, Yi-Fei,Lu, Shan,Ou, Ying-Jie,et al. The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2024,716:12.
APA Xuan, Yi-Fei.,Lu, Shan.,Ou, Ying-Jie.,Bao, Xu-Bin.,Huan, Xia-Juan.,...&Wang, Ying-Qing.(2024).The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,716,12.
MLA Xuan, Yi-Fei,et al."The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 716(2024):12.

入库方式： OAI收割

来源：上海药物研究所

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