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

Abstract

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.

Osteopontin Promotes Vascular Endothelial Growth Factor–Dependent Breast Tumor Growth and Angiogenesis via Autocrine and Paracrine Mechanisms

“…A and B, analysis of human breast tumor clinical specimens with different pathologic grades. Human breast tumor specimens (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) were collected from local hospital with informed consent. The tumor grading was performed by histopathologic analysis using a modified Scarff-Bloom-Richardson system.…”

“…Alternative exon splicing results in four isoforms of VEGF (VEGF 121 , VEGF 165 , VEGF 189 , and VEGF 206 ), and among them, VEGF 165 is the predominant one that plays a major role in tumor angiogenesis (7,8). Recent data show that the functions of VEGF may not be limited to endothelial cells but also play important roles in survival, proliferation, and migration in tumor cells (9,10).…”

Molecular genetics and racial disparities of uterine leiomyomas

“…28,29 On the other hand, 2-methoxy oestradiol has been demonstrated to possess a mitogenic effect on different cell types. [30][31][32] Therefore, the high-activity COMT genotype (Val/Val) would derive rapid and efficient conversion of the anti-oestrogenic metabolite (2-hydroxy oestradiol) into the more mitogenic counterpart (2-methoxy oestradiol), thus creating a high oestrogenic cellular milieu. Conversely, the low-activity COMT genotype (Met/Met) would lead to the accumulation of 2-hydroxy oestradiol, creating a low oestrogenic environment.…”

Treatment with an inhibitor of catechol-O-methyltransferase activity reduces preterm birth and impedes cervical resistance to stretch in pregnant rats

“…Catecholestrogens are the major metabolites produced during estrogen metabolism (Ball & Knuppen 1980). The catecholestrogens, 2-or 4-hydroxyestrogen, can act as estrogen antagonists (Vandewalle & Lefebvre 1989, Bradlow 1996, Al-Hendy & Salama 2006, while their methylated counterparts, 2-or 4-methoxyestrogen, can act as estrogen agonists in multiple biologic assays (Banerjee et al 2003, Lippert et al 2003, Liu & Zhu 2004, Sutherland et al 2005. In this study, we monitored the longitudinal changes in urinary 2-hydroxyestrogen as an indirect indicator for the changes of estrogen metabolism in pregnant rats before, during, and after pregnancy (Fig.…”

“…In estrogen metabolism, COMT converts the catecholestrogens, 2-and 4 hydroxyestrogen, to 2-and 4-methoxyestrogen respectively (Creveling 2003). The catecholestrogens, 2-or 4-hydroxyestrogen, can act as estrogen antagonists (Vandewalle & Lefebvre 1989, Bradlow 1996, Al-Hendy & Salama 2006) while their methylated counterparts, 2-or 4-methoxyestrogen, can act as estrogen agonists in multiple biologic assays (Banerjee et al 2003, Lippert et al 2003, Liu & Zhu 2004, Sutherland et al 2005. COMT is present in many types of tissues, including those involved in reproduction, such as the placenta (Castren & Saarikoski 1974, Barnea et al 1988, the decidua vera (Casey & MacDonald 1983), the myometrium (Al-Hendy & Salama 2006, Wentz et al 2006, and the endometrium (EN; Briggs & Briggs 1973, Casey & MacDonald 1983, Al-Hendy & Salama 2006, Salih et al 2007a.…”