Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2
Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2
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DOI：
10.1074/jbc.m109.064162
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发表时间：
2010-04-02
影响因子：
4.8
通讯作者：
Spiegel, Sarah
中科院分区：
文献类型：
--
作者：
Takabe, Kazuaki;Kim, Roger H.;Spiegel, Sarah
1-磷酸鞘氨醇（S1 P）是一种由鞘氨醇激酶同工酶（SphK 1和SphK 2）产生的强效鞘脂介质，可调节多种细胞过程，这些过程对乳腺癌进展至关重要，并以自分泌和/或旁分泌方式发挥作用。在这里，我们表明，SphK 1，而不是SphK 2，增加S1 P从MCF-7细胞的输出。而对于雌二醇（E-2）和表皮生长因子激活的SphK 1和S1 P的产生，只有E-2刺激MCF-7细胞快速释放S1 P和二氢-S1 P。E-2诱导的S1 P和二氢-S1 P输出需要雌激素受体α，而不是GPR 30，并且被药物抑制剂或ABCC 1（多药耐药蛋白1）或ABCG 2（乳腺癌耐药蛋白）的基因沉默抑制。抑制这些转运蛋白也阻断了E2诱导的ERK 1/2激活，表明E-2通过S1 P下游信号激活ERK。综上所述，我们的研究结果表明，E-2诱导出口的S1 P介导的ABCC 1和ABCG 2转运蛋白和随后的激活S1 P受体可能有助于非基因组信号的E-2乳腺癌的病理生理学重要。
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 E2-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.