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

Autor: Francis R LeBlanc, Thomas P. Loughran, Jeremy A. Hengst, Jong K. Yun, David J. Feith, Valerie S. Calvert, Emanuel F. Petricoin, Todd E. Fox, Xin Liu
Rok vydání: 2015
Předmět:
Cancer Research
Ceramide
animal structures
Cell Survival
Lymphocyte
Sphingosine kinase
Gene Expression
Antineoplastic Agents
Apoptosis
Biology
p38 Mitogen-Activated Protein Kinases
chemistry.chemical_compound
medicine
Humans
Enzyme Inhibitors
Phosphorylation
Janus Kinases
Mitogen-Activated Protein Kinase 1
Pharmacology
Sphingolipids
Mitogen-Activated Protein Kinase 3
Sphingosine
JNK Mitogen-Activated Protein Kinases
medicine.disease
Sphingolipid
Mitochondria
Cell biology
G2 Phase Cell Cycle Checkpoints
Leukemia
Large Granular Lymphocytic
Phosphotransferases (Alcohol Group Acceptor)
STAT Transcription Factors
Leukemia
SPHK2
Hydrazines
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Oncology
chemistry
Sphingosine kinase 1
Caspases
Cancer research
biology.protein
Pyrazoles
Molecular Medicine
human activities
Research Paper
Signal Transduction
Zdroj: Cancer Biology & Therapy. 16:1830-1840
ISSN: 1555-8576
1538-4047
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: