Abstract
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 (E(2)) and epidermal growth factor-activated SphK1 and production of S1P, only E(2) stimulated rapid release of S1P and dihydro-S1P from MCF-7 cells. E(2)-induced S1P and dihydro-S1P export required estrogen receptor-alpha, 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 E(2)-induced activation of ERK1/2, indicating that E(2) activates ERK via downstream signaling of S1P. Taken together, our findings suggest that E(2)-induced export of S1P mediated by ABCC1 and ABCG2 transporters and consequent activation of S1P receptors may contribute to nongenomic signaling of E(2) important for breast cancer pathophysiology.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism*
-
Blotting, Western
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism*
-
Cell Line, Tumor
-
Epidermal Growth Factor / pharmacology
-
ErbB Receptors / genetics
-
ErbB Receptors / metabolism
-
Estradiol / pharmacology*
-
Estrogens / pharmacology*
-
Humans
-
Lysophospholipids / metabolism*
-
Mitogen-Activated Protein Kinase 1 / genetics
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / genetics
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Multidrug Resistance-Associated Proteins / genetics
-
Multidrug Resistance-Associated Proteins / metabolism*
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Phosphotransferases (Alcohol Group Acceptor) / genetics
-
Phosphotransferases (Alcohol Group Acceptor) / metabolism
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Spectrometry, Mass, Electrospray Ionization
-
Sphingosine / analogs & derivatives*
-
Sphingosine / metabolism
Substances
-
ABCG2 protein, human
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters
-
Estrogens
-
Lysophospholipids
-
Multidrug Resistance-Associated Proteins
-
Neoplasm Proteins
-
RNA, Messenger
-
sphingosine 1-phosphate
-
Estradiol
-
Epidermal Growth Factor
-
Phosphotransferases (Alcohol Group Acceptor)
-
sphingosine kinase
-
ErbB Receptors
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Sphingosine
-
multidrug resistance-associated protein 1