title: Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia.
abstract: Sphingolipid metabolism has been identified as a potential therapeutic target in cancer. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and -2 (SPHK1 and SPHK2). Elevated SPHK1 has been found in numerous cancer types and been shown to contribute to survival, chemotherapeutic resistance and malignancy. However, its role in large granular Natural Killer (NK) large granular lymphocyte (LGL) leukemia has not been investigated. Here, we examine SPHK1 as a therapeutic target in LGL leukemia. We found that SPHK1 is overexpressed in peripheral blood mononuclear cells (PBMCs) from LGL leukemia patients which results in elevated S1P in the sera. The use of SPHK1 inhibitors, SKI-II or SKI-178, decreased leukemic NK cell viability and induced caspase-dependent apoptosis. SKI-II and SKI-178 restored the sphingolipid balance by increasing ceramide and decreasing S1P in leukemic NKL cells. SKI-II and SKI-178 also induced apoptosis in primary NK-LGLs from leukemia patients. Mechanistic studies in NK-LGL cell lines demonstrated that SKI-178 and SKI-II induced cell cycle arrest at G2/M. We found that SKI-178 induced phosphorylation of Bcl-2 at Ser70, and that this was dependent on CDK1. We further show that SPHK1 inhibition with SKI-178 leads to decreased JAK-STAT signaling. Our data demonstrate that SPHK1 represents a novel therapeutic target for the treatment of NK-LGL leukemia.
authors.affiliation: a Penn State Hershey Cancer Institute; Penn State College of Medicine ; Hershey , PA USA.|b University of Virginia Cancer Center; University of Virginia ; Charlottesville , VA USA.
authors.forename: Francis R
authors.initials: FR
authors.lastname: LeBlanc
authors.affiliation: a Penn State Hershey Cancer Institute; Penn State College of Medicine ; Hershey , PA USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: c Department of Pharmacology ; Penn State College of Medicine ; Hershey , PA USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hengst
authors.affiliation: b University of Virginia Cancer Center; University of Virginia ; Charlottesville , VA USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Fox
authors.affiliation: d Center for Applied Proteomics and Molecular Medicine; George Mason University ; Manassas , VA USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Calvert
authors.affiliation: d Center for Applied Proteomics and Molecular Medicine; George Mason University ; Manassas , VA USA.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: c Department of Pharmacology ; Penn State College of Medicine ; Hershey , PA USA.
authors.forename: Jong
authors.initials: J
authors.lastname: Yun
authors.affiliation: b University of Virginia Cancer Center; University of Virginia ; Charlottesville , VA USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.affiliation: b University of Virginia Cancer Center; University of Virginia ; Charlottesville , VA USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D004791:Enzyme Inhibitors; D006834:Hydrazines; D048031:JNK Mitogen-Activated Protein Kinases; D053612:Janus Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D050791:STAT Transcription Factors; D013107:Sphingolipids; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C556358:N'-((1E)-1-(3,4-dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide
keywords: LGL leukemia; SKI-178,SKI-II; apoptosis; large granular lymphocyte; natural killer; sphingosine kinase 1