title: Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer.
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.
authors.affiliation: Tulane Department of Pharmacology Section of Hematology and Medical Oncology, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Antoon
authors.forename: William D
authors.initials: WD
authors.lastname: Meacham
authors.forename: Melyssa R
authors.initials: MR
authors.lastname: Bratton
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Slaughter
authors.forename: Lyndsay V
authors.initials: LV
authors.lastname: Rhodes
authors.forename: Hasina B
authors.initials: HB
authors.lastname: Ashe
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wiese
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Beckman
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D047628:Estrogen Receptor alpha; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013058:Mass Spectrometry; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D017853:Phosphotransferases (Alcohol Group Acceptor); D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C506487:ESR1 protein, human