Abstract
Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions. However, the role of S1P signaling in tumorigenesis remains to be elucidated. In this study, we show that S1P receptor subtype 3 (S1P₃) is markedly up-regulated in a subset of lung adenocarcinoma cells compared to normal lung epithelial cells. Specific knockdown of S1P₃ receptors inhibits proliferation and anchorage-independent growth of lung adenocarcinoma cells. Mechanistically, we demonstrate that S1P₃ signaling increases epidermal growth factor receptor (EGFR) expression via the Rho kinase (ROCK) pathway in lung adenocarcinoma cells. Nuclear run-off analysis indicates that S1P/S1P₃ signaling transcriptionally increases EGFR expression. Knockdown of S1P₃ receptors diminishes the S1P-stimulated EGFR expression in lung adenocarcinoma cells. Moreover, S1P treatment greatly enhances EGF-stimulated colony formation, proliferation and invasion of lung adenocarcinoma cells. Together, these results suggest that the enhanced S1P₃-EGFR signaling axis may contribute to the tumorigenesis or progression of lung adenocarcinomas.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma of Lung
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Animals
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Carcinoma, Lewis Lung / genetics
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Carcinoma, Lewis Lung / metabolism*
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Cell Line, Tumor
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Cell Movement*
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Cell Proliferation*
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Epidermal Growth Factor / metabolism
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lysophospholipids / metabolism
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Mice
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Neoplasm Invasiveness
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RNA Interference
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RNA, Messenger / metabolism
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / metabolism*
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Signal Transduction*
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Sphingosine / analogs & derivatives
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Sphingosine / metabolism
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Sphingosine-1-Phosphate Receptors
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Time Factors
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Transcriptional Activation
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Transfection
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Up-Regulation
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rho-Associated Kinases / metabolism
Substances
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Lysophospholipids
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RNA, Messenger
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Receptors, Lysosphingolipid
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S1pr3 protein, mouse
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Sphingosine-1-Phosphate Receptors
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sphingosine 1-phosphate
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Epidermal Growth Factor
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EGFR protein, human
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ErbB Receptors
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rho-Associated Kinases
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Sphingosine