Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: The role of sphingosine 1-phosphate receptor-4.

Abstract

We demonstrate that pre-treatment of estrogen receptor negative MDA-MB-231 breast cancer cells containing ectopically expressed HA-tagged sphingosine 1-phosphate receptor-2 (S1P2) with the sphingosine kinase 1/2 inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) or the sphingosine kinase 2 selective inhibitor (R)-FTY720 methyl ether (ROMe) or sphingosine kinase 2 siRNA induced the translocation of HA-tagged S1P2 and Y416 phosphorylated c-Src to the nucleus of these cells. This is associated with reduced growth of HA-tagged S1P2 over-expressing MDA-MB-231 cells. Treatment of HA-S1P2 over-expressing MDA-MB-231 cells with the sphingosine 1-phosphate receptor-4 (S1P4) antagonist CYM50367 or with S1P4 siRNA also promoted nuclear translocation of HA-tagged S1P2. These findings identify for the first time a signaling pathway in which sphingosine 1-phosphate formed by sphingosine kinase 2 binds to S1P4 to prevent nuclear translocation of S1P2 and thereby promote the growth of estrogen receptor negative breast cancer cells.

• Authors: Jan Ohotski, Hugh Rosen, Robert Bittman, Susan Pyne, Nigel J Pyne
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 5 Pg. 1040-7 (May 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 24486401 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol
• Lysophospholipids
• Propylene Glycols
• RNA, Small Interfering
• Receptors, Estrogen
• Receptors, Lysosphingolipid
• S1PR2 protein, human
• Sphingosine-1-Phosphate Receptors
• Thiazoles
• sphingosine 1-phosphate
• Tyrosine
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human
• Fingolimod Hydrochloride
• Sphingosine

Topics

• Breast Neoplasms (metabolism, pathology)
• CSK Tyrosine-Protein Kinase
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Female
• Fingolimod Hydrochloride
• Humans
• Lysophospholipids (metabolism)
• Phosphorylation (drug effects)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, genetics, metabolism)
• Propylene Glycols (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Receptors, Estrogen (genetics, metabolism)
• Receptors, Lysosphingolipid (analysis, antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Sphingosine (analogs & derivatives, metabolism, pharmacology)
• Sphingosine-1-Phosphate Receptors
• Thiazoles (pharmacology)
• Tyrosine (metabolism)
• src-Family Kinases (metabolism)