Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer.
Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer.
复制标题
鞘氨醇激酶同种型的药理抑制会改变人类乳腺癌中的雌激素受体信号传导。
DOI：
10.1530/jme-10-0116
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发表时间：
2011-06
影响因子：
3.5
通讯作者：
Beckman BS
中科院分区：
文献类型：
--
作者：
Antoon JW;Meacham WD;Bratton MR;Slaughter EM;Rhodes LV;Ashe HB;Wiese TE;Burow ME;Beckman BS
最近，鞘脂信号通路和类固醇激素之间的串扰被认为是可能的治疗靶点。鞘氨醇激酶（skhingosine kinase， SK）是将促凋亡神经酰胺代谢为促存活鞘氨醇-1-磷酸（S1P）的关键酶，是一种很有前景的实体肿瘤治疗靶点。在这项研究中，我们检测了药物抑制S1P形成阻断雌激素信号作为乳腺癌靶向治疗的能力。我们发现Sphk1/2选择性抑制剂(SK inhibitor (SKI))-II)可以抑制乳腺癌的生存、克隆生存和增殖。此外，SKI-II剂量依赖性地降低了雌激素刺激的雌激素反应元件转录活性，并降低了雌激素受体（ER）调控基因孕激素受体和类固醇衍生因子-1的mRNA水平。这种抑制剂直接在拮抗剂配体结合区域与内质网结合。综上所述，我们的研究结果表明，在乳腺癌中，SKIs具有作为新型ER信号抑制剂的能力。
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.