Nakatani Kaname, Horinouchi Junichi, Yabu Yasuyoshi, Wada Hideo, Nobori Tsutomu
Department of Laboratory Medicine, Mie University School of Medicine, Mie 514-8507, Japan.
Oncol Rep. 2004 Oct;12(4):833-6.
The endothelial nitric oxide synthase (eNOS) gene is induced by a variety of extracellular signals and NOS plays a key role in many physiological as well as pathological processes, including tumorgenesis. Some studies showed a positive correlation between the level of NOS protein and progression of malignancy in human breast cancer. In this study, we examined eNOS mRNA expression in human breast cancer cell lines. MCF-7 cells, which showed an estrogen receptor positive phenotype, were treated with estradiol or LiCl, a selective inhibitor of glycogen synthase kinase (GSK)-3beta. Both estradiol and LiCl enhanced the expression of eNOS mRNA with the phosphorylation of GSK-3beta, but not Akt. The induction was completely suppressed by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002, but not by PD98059, MEK-1 inhibitor nor rapamycin, p70S6 kinase inhibitor. We conclude that the estradiol-induced eNOS expression is modulated by PI3-kinase-dependent GSK-3beta pathway.
内皮型一氧化氮合酶（eNOS）基因受多种细胞外信号诱导，一氧化氮合酶在包括肿瘤发生在内的许多生理和病理过程中起关键作用。一些研究表明，一氧化氮合酶蛋白水平与人类乳腺癌的恶性进展呈正相关。在本研究中，我们检测了人乳腺癌细胞系中eNOS mRNA的表达。具有雌激素受体阳性表型的MCF-7细胞用雌二醇或糖原合酶激酶（GSK）-3β的选择性抑制剂氯化锂处理。雌二醇和氯化锂均通过GSK-3β的磷酸化增强了eNOS mRNA的表达，但对Akt无此作用。磷脂酰肌醇3-激酶（PI3-激酶）抑制剂LY294002可完全抑制这种诱导作用，但MEK-1抑制剂PD98059或p70S6激酶抑制剂雷帕霉素则不能。我们得出结论，雌二醇诱导的eNOS表达受PI3-激酶依赖性GSK-3β途径调节。
