2-Methoxyestradiol causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells

Salama A. Salama, Concepcion R. Diaz-Arrastia, Gokhan S. Kilic, Marwa W. Kamel

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Objective: To investigate the effects and the mechanism of action of 2-methoxyestradiol (2ME2) on transforming growth factor (TGF) β3-induced profibrotic response in immortalized human uterine fibroid smooth muscle (huLM) cells. Design: Laboratory study. Setting: University research laboratory. Patients(s): Not applicable. Interventions(s): Not applicable. Main Outcome Measure(s): huLM cells were treated with TGF-β3 (5 ηg/mL) in the presence or absence of specific Smad3 inhibitor SIS3 (1 μmol/L), inhibitor of the PI3K/Akt (LY294002, 10 μmol/L), or 2ME 2 (0.5 μmol/L), and the expression of collagen (Col) type I(αI), Col III(αI), plasminogen activator inhibitor (PAI) 1, connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) were determined by real-time reverse-transcription polymerase chain reaction and immunoblotting. The effect of 2ME2 on Smad-microtubule binding was evaluated by coimmunoprecipitation. Result(s): Our data revealed that TGF-β3-induced fibrogenic response in huLM is mediated by both Smad-dependent and Smad-independent PI3K/Akt/mTOR signaling pathways. 2ME2 abrogates TGF-β3-induced expression of Col I(αI), Col III(αI), PAI-1, CTGF, and α-SMA. Molecularly, 2ME2 ameliorates TGF-β3-induced Smad2/3 phosphorylation and nuclear translocation. In addition, 2ME2 inhibits TGF-β3-induced activation of the PI3K/Akt/mTOR pathway. Conclusion(s): TGF-β3-induced profibrotic response in fibroid cells is mediated by Smad-dependent and Smad-independent PI3K/Akt/mTOR pathways. 2ME2 inhibits TGF-β3 profibrotic effects in huLM cells by ameliorating both Smad-dependent and Smad-independent signaling pathways.

Original languageEnglish (US)
Pages (from-to)178-184.e1
JournalFertility and Sterility
Volume98
Issue number1
DOIs
StatePublished - Jul 2012

Keywords

  • 2-methoxyestradiol
  • Transforming growth factor β signaling
  • uterine fibroids

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

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