Banerjee Samarendra N, Sengupta Krishanu, Banerjee Snigdha, Saxena Neela K, Banerjee Sushanta K
Cancer Research Unit, V.A. Medical Center, Kansas City, KS, USA.
Neoplasia. 2003 Sep-Oct;5(5):417-26. doi: 10.1016/s1476-5586(03)80044-1.
2-Methoxyestradiol (2-ME2) was reported to elicit both stimulation and inhibition of tumor angiogenesis and growth depending on the dosage used. However, the mechanism(s) of the biphasic action of 2-ME2 has been elusive. Here we describe a regulatory role of vascular endothelial growth factor-A (VEGF-A) in the biphasic effects on estrogen receptor (ER)+ GH3 rat pituitary tumor cells and MCF-7 human breast tumor cells depending on the dosage of 2-ME2 used. We observed that acute exposure to 2-ME2, irrespective of dosage, did not alter cellular proliferation, but enhanced the VEGF-A mRNA level. As the treatment duration increased, biphasic effect was elicited. A concentration of 1 microM 2-ME2 increased both cell proliferation and VEGF-A levels in these cells, whereas higher doses exhibited reversed impact. A low dose of 2-ME2 also increased the VEGF-A mRNA expression in ER-alpha-transfected human mammary epithelial cells (HMECs). The effect was reversed in ER- cells. The enhanced expression of VEGF-A mRNA could be blocked by the pure estrogen antagonist, ICI 182,780, and reveal that the upregulation of VEGF-A expression by 2-ME2 is mediated through ER-alpha. Furthermore, the biphasic effect of 2-ME2 on cell proliferation can be modulated by administrating VEGF-A antibodies or VEGF-A proteins. Studies also demonstrate that the VEGF-A protein, induced by 2-ME2, is functionally active and upregulates the proliferation of adjacent endothelial cells.
据报道，2-甲氧基雌二醇（2-ME2）根据所用剂量可引发肿瘤血管生成和生长的刺激与抑制作用。然而，2-ME2双相作用的机制一直难以捉摸。在此，我们描述了血管内皮生长因子-A（VEGF-A）在2-ME2对雌激素受体（ER）阳性的GH3大鼠垂体瘤细胞和MCF-7人乳腺瘤细胞的双相作用中的调节作用，该作用取决于所用2-ME2的剂量。我们观察到，急性暴露于2-ME2，无论剂量如何，均不会改变细胞增殖，但会提高VEGF-A mRNA水平。随着处理时间的增加，引发了双相效应。1 microM的2-ME2浓度增加了这些细胞中的细胞增殖和VEGF-A水平，而更高剂量则表现出相反的影响。低剂量的2-ME2也增加了ER-α转染的人乳腺上皮细胞（HMECs）中VEGF-A mRNA的表达。在ER阴性细胞中该效应则相反。VEGF-A mRNA表达的增强可被纯雌激素拮抗剂ICI 182,780阻断，这表明2-ME2对VEGF-A表达的上调是通过ER-α介导的。此外，2-ME2对细胞增殖的双相作用可通过施用VEGF-A抗体或VEGF-A蛋白来调节。研究还表明，由2-ME2诱导的VEGF-A蛋白具有功能活性，并上调相邻内皮细胞的增殖。
