2-methoxyestradiol exhibits a biphasic effect on VEGF-A in tumor cells and upregulation is mediated through ER-α:: A possible signaling pathway associated with the impact of 2-ME2 on proliferative cells
2-methoxyestradiol exhibits a biphasic effect on VEGF-A in tumor cells and upregulation is mediated through ER-α:: A possible signaling pathway associated with the impact of 2-ME2 on proliferative cells
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DOI：
10.1016/s1476-5586(03)80044-1
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发表时间：
2003-09-01
期刊：
影响因子：
4.8
通讯作者：
Banerjee, SK
中科院分区：
文献类型：
--
作者：
Banerjee, SN;Senupta, K;Banerjee, SK
据报道，2-甲氧基雌二醇（2-ME2）可以刺激和抑制肿瘤血管生成和生长，这取决于使用的剂量。然而，2-ME2双相作用的机制尚不清楚。在这里，我们描述了血管内皮生长因子- a （VEGF-A）在雌激素受体（ER）（+） GH3大鼠垂体肿瘤细胞和MCF-7人乳腺肿瘤细胞的双相作用中的调节作用，这取决于使用的2-ME2的剂量。我们观察到，急性暴露于2-ME2，无论剂量如何，都不会改变细胞增殖，但会提高VEGF-A mRNA水平。随着治疗时间的延长，双相效应出现。1mum - 2-ME2浓度增加了这些细胞的细胞增殖和VEGF-A水平，而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。这种效应在ER细胞中被逆转。纯雌激素拮抗剂ICI 182780可阻断VEGF-A mRNA表达的增强，提示2-ME2上调VEGF-A表达是通过er - α介导的。此外，2-ME2对细胞增殖的双相效应可以通过给药VEGF-A抗体或VEGF-A蛋白来调节。研究还表明，2-ME2诱导的VEGF-A蛋白具有功能活性，可上调邻近内皮细胞的增殖。
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 muM 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.