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GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells

Omar Flores1, Kerry L Burnstein

  • 1Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, R-189, Room 6155 Rosenstiel Building, Miami, Florida 33136, USA.

Endocrinology
|August 27, 2010
PubMed

Insights

1,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by regulating GADD45γ. This vitamin D metabolite

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] is known to inhibit prostate cancer cell proliferation by affecting cell cycle progression.
  • The precise mechanisms underlying 1,25-(OH)2D3's antiproliferative effects, while requiring the vitamin D receptor, are not fully understood.
  • A 1,25-(OH)2D3-resistant prostate cancer cell line (LNCaP) was developed, retaining vitamin D receptors but lacking growth inhibition by 1,25-(OH)2D3.

Purpose of the Study:

  • To elucidate the molecular mechanisms of 1,25-(OH)2D3's antiproliferative effects in prostate cancer cells.
  • To identify novel genes regulated by 1,25-(OH)2D3 in prostate cancer.
  • To establish the role of identified genes, specifically GADD45γ and MIG6, in vitamin D-mediated growth inhibition.

Main Methods:

  • Gene expression profiling was performed on LNCaP and 1,25-(OH)2D3-resistant cells to identify differentially expressed genes.
  • The function of identified genes (GADD45γ and MIG6) was investigated through ectopic expression in prostate cancer cell lines (LNCaP, ALVA31).
  • Cell cycle progression and proliferation were analyzed following gene manipulation and 1,25-(OH)2D3 treatment.

Main Results:

  • Gene expression profiling identified two novel 1,25-(OH)2D3-inducible genes: GADD45γ and MIG6, in responsive LNCaP cells but not in resistant cells.
  • GADD45γ up-regulation correlated with 1,25-(OH)2D3-induced growth inhibition; ectopic GADD45γ expression caused G1 cell cycle arrest and proliferation inhibition.
  • 1,25-(OH)2D3-induced GADD45γ expression was independent of androgen receptor signaling, suggesting a distinct pathway for vitamin D-mediated growth inhibition.

Conclusions:

  • GADD45γ is identified as a novel 1,25-(OH)2D3-regulated gene that mediates growth inhibition in prostate cancer cells.
  • Ectopic expression of GADD45γ effectively inhibits prostate cancer cell proliferation and induces G1 cell cycle arrest, mimicking 1,25-(OH)2D3 effects.
  • The induction of GADD45γ by 1,25-(OH)2D3 presents a potential biomarker for therapeutic response in prostate cancer treatment.

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