Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia

Francis R. LeBlanc, Xin Liu, Jeremy Hengst, Todd Fox, Valerie Calvert, Emanuel F. Petricoin, Jong Yun, David J. Feith, Thomas P. Loughran

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1830-1840
Number of pages11
JournalCancer Biology and Therapy
Volume16
Issue number12
DOIs
StatePublished - Dec 2 2015

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Large Granular Lymphocytic Leukemia
Cell Death
Sphingolipids
G2 Phase Cell Cycle Checkpoints
Apoptosis
Neoplasms
Ceramides
Therapeutics
Caspases
Natural Killer Cells
N'-((1E)-1-(3,4-dimethoxyphenyl)ethylidene)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide
sphingosine kinase
Blood Cells
Cell Survival
Phosphorylation
Lymphocytes
Cell Line
Survival
Serum

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

LeBlanc, Francis R. ; Liu, Xin ; Hengst, Jeremy ; Fox, Todd ; Calvert, Valerie ; Petricoin, Emanuel F. ; Yun, Jong ; Feith, David J. ; Loughran, Thomas P. / Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia. In: Cancer Biology and Therapy. 2015 ; Vol. 16, No. 12. pp. 1830-1840.
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Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia. / LeBlanc, Francis R.; Liu, Xin; Hengst, Jeremy; Fox, Todd; Calvert, Valerie; Petricoin, Emanuel F.; Yun, Jong; Feith, David J.; Loughran, Thomas P.

In: Cancer Biology and Therapy, Vol. 16, No. 12, 02.12.2015, p. 1830-1840.

Research output: Contribution to journalArticle

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T1 - Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia

AU - LeBlanc, Francis R.

AU - Liu, Xin

AU - Hengst, Jeremy

AU - Fox, Todd

AU - Calvert, Valerie

AU - Petricoin, Emanuel F.

AU - Yun, Jong

AU - Feith, David J.

AU - Loughran, Thomas P.

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AB - 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.

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