Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression
Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression
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DOI：
10.1074/jbc.m110.195826
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发表时间：
2011-06-03
影响因子：
4.8
通讯作者：
Sewer, Marion B.
中科院分区：
文献类型：
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作者：
Lucki, Natasha C.;Sewer, Marion B.
鞘脂代谢物，如神经酰胺（Cer）、鞘氨醇（SPH）和1-磷酸鞘氨醇（S1 P），参与了致癌作用的多个方面，包括细胞增殖、迁移、血管生成和肿瘤抗性。例如，Cer和S1 P水平之间的细胞平衡是细胞命运的重要决定因素，前者诱导凋亡，后者诱导有丝分裂。酸性神经酰胺酶（ASAH 1）通过将Cer水解成SPH，SPH被迅速磷酸化形成S1 P，在调节这两种代谢物的细胞内浓度中起关键作用。染料木黄酮是一种植物雌激素受体，主要作为雌激素受体的配体，以剂量依赖性方式对雌激素依赖性MCF-7细胞的增殖发挥激动剂和拮抗剂作用。染料木黄酮还可以通过G蛋白偶联的细胞表面受体GPR 30激活信号传导。基于生物活性鞘脂与肿瘤发生之间的关系，我们试图确定金雀异黄素对MCF-7乳腺癌细胞中ASAH 1转录的影响。我们在此表明，纳摩尔浓度的染料木素诱导ASAH 1转录通过GPR 30依赖性，百日咳毒素敏感的途径，需要激活的c-Src和细胞外信号调节激酶1/2（ERK 1/2）。该途径的激活促进组蛋白乙酰化和磷酸雌激素受体α和特异性蛋白-1向ASAH 1启动子的募集，最终导致神经酰胺酶活性增加。最后，我们表明，染料木黄酮刺激细胞周期蛋白B2的表达和细胞增殖的ASAH 1依赖的方式。总的来说，这些数据确定了染料木黄酮促进鞘脂代谢的机制，并支持ASAH 1在乳腺癌细胞生长中的作用。
Sphingolipid metabolites, such as ceramide (Cer), sphingosine (SPH), and sphingosine 1-phosphate (S1P), contribute to multiple aspects of carcinogenesis including cell proliferation, migration, angiogenesis, and tumor resistance. The cellular balance between Cer and S1P levels, for example, is an important determinant of cell fate, with the former inducing apoptosis and the later mitogenesis. Acid ceramidase (ASAH1) plays a pivotal role in regulating the intracellular concentration of these two metabolites by hydrolyzing Cer into SPH, which is rapidly phosphorylated to form S1P. Genistein is a phytoestrogen isoflavone that exerts agonist and antagonist effects on the proliferation of estrogen-dependent MCF-7 cells in a dose-dependent manner, primarily as a ligand for estrogen receptors. Genistein can also activate signaling through GPR30, a G-protein-coupled cell surface receptor. Based on the relationship between bioactive sphingolipids and tumorigenesis, we sought to determine the effect of genistein on ASAH1 transcription in MCF-7 breast cancer cells. We show herein that nanomolar concentrations of genistein induce ASAH1 transcription through a GPR30-dependent, pertussis toxin-sensitive pathway that requires the activation of c-Src and extracellular signal regulated kinase 1/2 (ERK1/2). Activation of this pathway promotes histone acetylation and recruitment of phospho-estrogen receptor alpha and specificity protein-1 to the ASAH1 promoter, ultimately culminating in increased ceramidase activity. Finally, we show that genistein stimulates cyclin B2 expression and cell proliferation in an ASAH1-dependent manner. Collectively, these data identify a mechanism through which genistein promotes sphingolipid metabolism and support a role for ASAH1 in breast cancer cell growth.