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

Cell Signal. 2014 May;26(5):1040-7. doi: 10.1016/j.cellsig.2014.01.023. Epub 2014 Jan 29.

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.

Keywords: Cancer; Growth; Nuclear signaling; Sphingosine 1-phosphate; Sphingosine 1-phosphate receptors; Sphingosine kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / 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
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Propylene Glycols / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Receptors, Lysosphingolipid / analysis
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • Signal Transduction
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Sphingosine-1-Phosphate Receptors
  • Thiazoles / pharmacology
  • Tyrosine / metabolism
  • src-Family Kinases / metabolism*

Substances

  • 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