2-Methoxyestradiol exhibits a biphasic effect on VEGF-A in tumor cells and upregulation is mediated through ER-alpha: a possible signaling pathway associated with the impact of 2-ME2 on proliferative cells.
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.
Banerjee
Samarendra N
SN
Cancer Research Unit, V.A. Medical Center, Kansas City, KS, USA. sbanerjee2@kumc.edu
Sengupta
Krishanu
K
Banerjee
Snigdha
S
Saxena
Neela K
NK
Banerjee
Sushanta K
SK
D000077584:2-Methoxyestradiol; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D006801:Humans; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D000077267:Fulvestrant; D004958:Estradiol; D000077584:2-Methoxyestradiol; D001973:Bromodeoxyuridine; D013936:Thymidine