FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels

doi:10.1371/journal.pone.0103033

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	FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels
	Chen, Limin 1,2; Luo, Liu-Fei 1; Lu, Junyan 2; Li, Lianchun 2; Liu, Yuan-Fang 1; Wang, Jiang2 ; Liu, Hong2 ; Song, Heng 3; Jiang, Hualiang2 ; Chen, Sai-Juan 1
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).