Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer

J Mol Endocrinol. 2011 Apr 28;46(3):205-16. doi: 10.1530/JME-10-0116. Print 2011 Jun.

Abstract

Recently, crosstalk between sphingolipid signaling pathways and steroid hormones has been illuminated as a possible therapeutic target. Sphingosine kinase (SK), the key enzyme metabolizing pro-apoptotic ceramide to pro-survival sphingosine-1-phosphate (S1P), is a promising therapeutic target for solid tumor cancers. In this study, we examined the ability of pharmacological inhibition of S1P formation to block estrogen signaling as a targeted breast cancer therapy. We found that the Sphk1/2 selective inhibitor (SK inhibitor (SKI))-II, blocked breast cancer viability, clonogenic survival and proliferation. Furthermore, SKI-II dose-dependently decreased estrogen-stimulated estrogen response element transcriptional activity and diminished mRNA levels of the estrogen receptor (ER)-regulated genes progesterone receptor and steroid derived factor-1. This inhibitor binds the ER directly in the antagonist ligand-binding domain. Taken together, our results suggest that SKIs have the ability to act as novel ER signaling inhibitors in breast carcinoma.

Publication types

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

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Computer Simulation
  • Estrogen Receptor alpha
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism*
  • Mass Spectrometry
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Thiazoles / pharmacology*

Substances

  • 4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol
  • Estrogen Receptor alpha
  • Isoenzymes
  • Thiazoles
  • estrogen receptor alpha, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase