Catechol-O-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells

Salama A. Salama, Marwa W. Kamel, Shaleen Botting, Sana M. Salih, Mostafa A. Borahay, Ahmed A. Hamed, Gokhan Kilic, Muhammad Saeed, Marian Y. Williams, Concepcion R. Diaz-Arrastia

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Abstract

Context: 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). Objectives: 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 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. Conclusions: COMT 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.

Original languageEnglish (US)
Article numbere7356
JournalPLoS One
Volume4
Issue number10
DOIs
StatePublished - Oct 7 2009

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catechol O-methyltransferase
Catechol O-Methyltransferase
Steroid Receptors
Leiomyoma
Microtubules
microtubules
Aromatase
cells
Hypoxia-Inducible Factor 1
Progesterone Receptors
Estrogen Receptors
human growth
estrogens
methylcobalamin-coenzyme M methyltransferase
2-methoxyestradiol
steroid receptors
collagen
cell proliferation
Cell proliferation
cytoplasm

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Salama, S. A., Kamel, M. W., Botting, S., Salih, S. M., Borahay, M. A., Hamed, A. A., ... Diaz-Arrastia, C. R. (2009). Catechol-O-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells. PLoS One, 4(10), [e7356]. https://doi.org/10.1371/journal.pone.0007356

Catechol-O-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells. / Salama, Salama A.; Kamel, Marwa W.; Botting, Shaleen; Salih, Sana M.; Borahay, Mostafa A.; Hamed, Ahmed A.; Kilic, Gokhan; Saeed, Muhammad; Williams, Marian Y.; Diaz-Arrastia, Concepcion R.

In: PLoS One, Vol. 4, No. 10, e7356, 07.10.2009.

Research output: Contribution to journalArticle

Salama, SA, Kamel, MW, Botting, S, Salih, SM, Borahay, MA, Hamed, AA, Kilic, G, Saeed, M, Williams, MY & Diaz-Arrastia, CR 2009, 'Catechol-O-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells', PLoS One, vol. 4, no. 10, e7356. https://doi.org/10.1371/journal.pone.0007356
Salama, Salama A. ; Kamel, Marwa W. ; Botting, Shaleen ; Salih, Sana M. ; Borahay, Mostafa A. ; Hamed, Ahmed A. ; Kilic, Gokhan ; Saeed, Muhammad ; Williams, Marian Y. ; Diaz-Arrastia, Concepcion R. / Catechol-O-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells. In: PLoS One. 2009 ; Vol. 4, No. 10.
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abstract = "Context: 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). Objectives: 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 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. Conclusions: COMT 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.",
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AU - Salih, Sana M.

AU - Borahay, Mostafa A.

AU - Hamed, Ahmed A.

AU - Kilic, Gokhan

AU - Saeed, Muhammad

AU - Williams, Marian Y.

AU - Diaz-Arrastia, Concepcion R.

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