FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels | |
Chen, Limin1,2; Luo, Liu-Fei1; Lu, Junyan2; Li, Lianchun2; Liu, Yuan-Fang1; Wang, Jiang2; Liu, Hong2; Song, Heng3; Jiang, Hualiang2; Chen, Sai-Juan1 | |
刊名 | PLOS ONE |
2014-07-22 | |
卷号 | 9期号:7 |
ISSN号 | 1932-6203 |
DOI | 10.1371/journal.pone.0103033 |
文献子类 | Article |
英文摘要 | The M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) represents an unmet challenge because of poor clinical outcomes in a sizable portion of patients. In this study, we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treating of multiple sclerosis, shows antitumorigenic activity against the Kasumi-1 cell line, xenograft mouse models and leukemic blasts isolated from AML-M2 patients with t(8; 21) translocation. Primary investigation indicated that FTY720 caused cell apoptosis through caspases and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. Treatment with FTY720 led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increase of pro-apoptotic ceramide levels, determined by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry based lipidomic approaches. Structural simulation model had also indicated that the direct binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8; 21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight for the drug development of treatment for AML-M2 leukemia. |
资助项目 | China 973 Program[2013CB733700] ; China 973 Program[2011CB510102] ; China 973 Program[2009CB918502] ; National Natural Science Foundation of China[81270622] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[81200373] ; National High Technology Research and Development Program of China[2012AA020302] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507-004] |
WOS关键词 | NEUTRAL SPHINGOMYELINASE ; LYMPHOCYTIC-LEUKEMIA ; CANCER-CELLS ; INHIBITOR ; FINGOLIMOD ; PATHWAY ; DEATH ; SPHINGOSINE-1-PHOSPHATE ; IDENTIFICATION ; TRANSLOCATION |
WOS研究方向 | Science & Technology - Other Topics |
语种 | 英语 |
出版者 | PUBLIC LIBRARY SCIENCE |
WOS记录号 | WOS:000339551100080 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/276981] |
专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
通讯作者 | Luo, Cheng |
作者单位 | 1.Shanghai Jiao Tong Univ, Sch Med, State Key Lab Med Genom, Shanghai Inst Hematol,Rui Jin Hosp, Shanghai 200030, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China; 3.E China Univ Sci & Technol, Dept Chem, Shanghai 200237, Peoples R China |
推荐引用方式 GB/T 7714 | Chen, Limin,Luo, Liu-Fei,Lu, Junyan,et al. FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels[J]. PLOS ONE,2014,9(7). |
APA | Chen, Limin.,Luo, Liu-Fei.,Lu, Junyan.,Li, Lianchun.,Liu, Yuan-Fang.,...&Li, Keqin Kathy.(2014).FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels.PLOS ONE,9(7). |
MLA | Chen, Limin,et al."FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels".PLOS ONE 9.7(2014). |
个性服务 |
查看访问统计 |
相关权益政策 |
暂无数据 |
收藏/分享 |
除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。
修改评论