Abstract
The sphingolipid metabolite, sphingosine-1-phosphate (S1P), formed by phosphorylation of sphingosine, has been implicated in cell growth, suppression of apoptosis, and angiogenesis. In this study, we have examined the contribution of intracellular S1P to tumorigenesis of breast adenocarcinoma MCF-7 cells. Enforced expression of sphingosine kinase type 1 (SPHK1) increased S1P levels and blocked MCF-7 cell death induced by anti-cancer drugs, sphingosine, and TNF-alpha. SPHK1 also conferred a growth advantage, as determined by proliferation and growth in soft agar, which was estrogen dependent. While both ERK and Akt have been implicated in MCF-7 cell growth, SPHK1 stimulated ERK1/2 but had no effect on Akt. Surprisingly, parental growth of MCF-7 cells was only weakly stimulated by S1P or dihydro-S1P, ligands for the S1P receptors which usually mediate growth effects. When injected into mammary fat pads of ovariectomized nude mice implanted with estrogen pellets, MCF-7/SPHK1 cells formed more and larger tumors than vector transfectants with higher microvessel density in their periphery. Collectively, our results suggest that SPHK1 may play an important role in breast cancer progression by regulating tumor cell growth and survival.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / enzymology
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Adenocarcinoma / pathology*
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Animals
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / enzymology
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Breast Neoplasms / pathology*
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Estrogens / metabolism
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Humans
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Lysophospholipids*
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Mammary Neoplasms, Experimental / enzymology
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasms, Hormone-Dependent / enzymology
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Neoplasms, Hormone-Dependent / pathology*
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Phosphotransferases (Alcohol Group Acceptor) / physiology*
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Receptors, Cell Surface / metabolism
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Receptors, Estrogen / metabolism
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Receptors, G-Protein-Coupled*
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Receptors, Lysophospholipid
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Sphingosine / analogs & derivatives*
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Sphingosine / metabolism
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
Substances
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Antineoplastic Agents
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Estrogens
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Lysophospholipids
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Receptors, Cell Surface
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Receptors, Estrogen
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Receptors, G-Protein-Coupled
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Receptors, Lysophospholipid
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sphingosine 1-phosphate
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Sphingosine