- Made available online as an Accepted Preprint 14 February 2011
Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer
- James W Antoon1,
- William D Meacham1,
- Melyssa R Bratton2,
- Evelyn M Slaughter1,
- Lyndsay V Rhodes2,
- Hasina B Ashe3,
- Thomas E Wiese3,
- Matthew E Burow2 and
- Barbara S Beckman1
- 1Tulane Department of Pharmacology
2Section of Hematology and Medical Oncology, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA
3Department of Pharmacy, Xavier University, 7325 Palmetto Street, New Orleans, Louisiana 70125, USA
- (Correspondence should be addressed to B S Beckman; Email: bbeckman{at}tulane.edu)
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.
- Revision received 1 February 2011
- Accepted 14 February 2011
- © 2011 Society for Endocrinology
