Abstract
ContextDevelopment 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).ObjectivesOur 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.ResultsOur data demonstrated that E2-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 α (ERα) 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 -1α (HIF-1 α) and the basal level as well as TNF-α-induced aromatase (CYP19) expression.ConclusionsCOMT over expression or treatment with 2ME stabilize microtubules, ameliorates E2-induced proliferation, inhibits ERα and PR signaling, and reduces HIF-1 α 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.
Highlights
Uterine leiomyomas are the most common benign gynecological tumors in reproductive age women
We studied the effect of COMT expression or treatment with 2ME (500 nM) on E2-induced proliferation of human leiomyoma cells. huLMW, human leiomyomas cells (huLM)-COMTKD, EM-COMTKI, or huLM cells treated with 500 nM of were plated in triplicate in 96
Prior to the principal experiments, we validated the functional significance of COMT expression on the 2ME level
Summary
Uterine leiomyomas are the most common benign gynecological tumors in reproductive age women. It is estimated that the incidence of uterine leiomyomas is over 80% in African-American women by age 50, whereas Caucasian women have an incidence of almost 70% at a similar age [1]. Uterine leiomyomas are benign tumors, they have a tremendous medical and economical impact. Uterine leiomyomas are the leading indication for hysterectomy in the United States [2]. Myomectomy and uterine artery embolization are common treatments; hysterectomy may be eventually required [3]. Medical treatments for leiomyomas are limited and suboptimal [4]
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