Catechol-o-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells.
BACKGROUND
Development of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT). Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM).


OBJECTIVE
Our objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells.


RESULTS
Our data demonstrated that E(2)-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM). This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1alpha (HIF-1 alpha) and the basal level as well as TNF-alpha-induced aromatase (CYP19) expression.


CONCLUSIONS
COMT over expression or treatment with 2ME stabilize microtubules, ameliorates E(2)-induced proliferation, inhibits ERalpha and PR signaling, and reduces HIF-1 alpha and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas.
Salama
Salama A
SA
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, USA. salama@bcm.tmc.edu
Kamel
Marwa W
MW
Botting
Shaleen
S
Salih
Sana M
SM
Borahay
Mostafa A
MA
Hamed
Ahmed A
AA
Kilic
Gokhan S
GS
Saeed
Muhammad
M
Williams
Marian Y
MY
Diaz-Arrastia
Concepcion R
CR
D000077584:2-Methoxyestradiol; D017209:Apoptosis; D001141:Aromatase / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000096:biosynthesis*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011980:Receptors, Progesterone / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism
D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D000077584:2-Methoxyestradiol; D001141:Aromatase; D002394:Catechol O-Methyltransferase