Inhibition of tumor cell proliferation in human uterine leiomyomas by vitamin D via Wnt/β-catenin pathway

Fertil Steril. 2019 Feb;111(2):397-407. doi: 10.1016/j.fertnstert.2018.10.008. Epub 2018 Nov 17.

Abstract

Objective: To assess the effect of vitamin D (VitD) on human uterine leiomyomas through Wnt/β-catenin pathway inhibition, apoptosis induction, and cell growth arrest.

Design: A prospective study comparing leiomyoma vs. myometrium tissues. Paired design study comparing human uterine leiomyoma primary (HULP) cells treated with or without VitD.

Setting: University hospital.

Patient(s): Human uterine leiomyoma and myometrium were collected from women (aged 35-52 years) without hormonal treatment.

Intervention(s): Samples were collected from women undergoing surgery due to symptomatic uterine leiomyoma pathology.

Main outcome measure(s): Uterine leiomyoma and myometrium tissues were analyzed by western blot (WB) to determine proliferation, Wnt/β-catenin, and apoptosis pathways. HULP cells were used to study VitD effect in cell proliferation (WB), cell cycle (flow cytometry), Wnt/β-catenin and apoptosis genes (polymerase chain reaction arrays), Wnt-related proteins (protein array), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL] assay).

Results: Human leiomyoma tissues compared with matched myometrium showed higher proliferation (fold change = 8.16; P=.0006) and altered Wnt/β-catenin pathway (fold change = 5.5; P<.0001), whereas no differences in apoptosis were observed. VitD induced cell growth arrest and decreased proliferation in HULP cells (fold change = 0.74; P=.007). Moreover, VitD decreased Wnt-pathway expression in HULP cells at gene (activity score = -0.775; P<.001) and protein levels. However, VitD did not induce apoptosis expression.

Conclusion: Increased proliferation and Wnt/β-catenin pathway deregulation play a role in the development and growth of leiomyomas, whereas apoptosis appears not to contribute. VitD exerts an antiproliferative action on HULP cells through cell growth arrest and Wnt/β-catenin pathway inhibition, but not through apoptosis regulation, suggesting VitD as an effective therapy to stabilize leiomyoma size and prevent its growth.

Keywords: Uterine leiomyoma; Wnt/β-catenin; apoptosis; cell growth arrest; vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leiomyoma / drug therapy*
  • Leiomyoma / genetics
  • Leiomyoma / metabolism
  • Leiomyoma / pathology
  • Middle Aged
  • Tumor Cells, Cultured
  • Uterine Neoplasms / drug therapy*
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / metabolism
  • Uterine Neoplasms / pathology
  • Vitamin D / pharmacology*
  • Wnt Signaling Pathway / drug effects*
  • Wnt Signaling Pathway / genetics

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Vitamin D