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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.

SUBMITTER: Antoon JW 

PROVIDER: S-EPMC4007162 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Antoon James W JW   Meacham William D WD   Bratton Melyssa R MR   Slaughter Evelyn M EM   Rhodes Lyndsay V LV   Ashe Hasina B HB   Wiese Thomas E TE   Burow Matthew E ME   Beckman Barbara S BS  

Journal of molecular endocrinology 20110428 3


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 selec  ...[more]

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