Lipids
Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2*

https://doi.org/10.1074/jbc.M109.064162Get rights and content
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Sphingosine 1-phosphate (S1P), a potent sphingolipid mediator produced by sphingosine kinase isoenzymes (SphK1 and SphK2), regulates diverse cellular processes important for breast cancer progression acting in an autocrine and/or paracrine manner. Here we show that SphK1, but not SphK2, increased S1P export from MCF-7 cells. Whereas for both estradiol (E2) and epidermal growth factor-activated SphK1 and production of S1P, only E2 stimulated rapid release of S1P and dihydro-S1P from MCF-7 cells. E2-induced S1P and dihydro-S1P export required estrogen receptor-α, not GPR30, and was suppressed either by pharmacological inhibitors or gene silencing of ABCC1 (multidrug resistant protein 1) or ABCG2 (breast cancer resistance protein). Inhibiting these transporters also blocked E2-induced activation of ERK1/2, indicating that E2 activates ERK via downstream signaling of S1P. Taken together, our findings suggest that E2-induced export of S1P mediated by ABCC1 and ABCG2 transporters and consequent activation of S1P receptors may contribute to nongenomic signaling of E2 important for breast cancer pathophysiology.

Receptors/Steroid/Thyroid
Signal Transduction/Sphingolipid
Transport/Multidrug
Lipid
Sphingolipid
ABC Transporters
Estradiol
Sphingosine Kinase
Sphingosine 1-Phosphate

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*

This work was supported, in whole or in part, by National Institutes of Health Grants R37GM043880 and R01CA61774 (to S. S.), Virginia Commonwealth University Grant BIRCWH K12HD055881, and Susan G. Komen for the Cure Career Catalyst Research Grant KG090510 (to K. T.).

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Supported by the SUMITOMO Life Social Welfare Services Foundation.