Constitutive activation of the mitogen-activated protein kinase pathway impairs vitamin D signaling in human prostate

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Zhentao Zhang1, Pavlo Kovalenko, Min Cui

  • 1Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana 47907-2059, USA.

Journal of Cellular Physiology
|May 1, 2010
PubMed

Insights

Prolonged activation of mitogen-activated protein kinase (MAPK) signaling impairs vitamin D action in prostate cells. This occurs due to RXRalpha phosphorylation, hindering co-activator recruitment and vitamin D-regulated gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Mitogen-activated protein kinase (MAPK) signaling is frequently activated in cancer.
  • 1,25 dihydroxyvitamin D (1,25(OH)(2)D(3)) has anti-cancer properties, including growth arrest and gene induction in prostate cells.
  • Dysregulation of vitamin D signaling is implicated in prostate cancer development.

Purpose of the Study:

  • To investigate the impact of prolonged MAPK activation on 1,25(OH)(2)D(3) action in human prostate epithelial cells.
  • To elucidate the molecular mechanisms by which MAPK signaling interferes with vitamin D-mediated transcription.
  • To determine the role of the VDR-RXR complex in this interaction.

Main Methods:

  • Utilized immortalized human prostate epithelial cell lines (RWPE1 and RWPE2).
  • Assessed the effects of 1,25(OH)(2)D(3) treatment, MAPK inhibition, and MAPK activation on cell growth and gene expression.
  • Employed molecular techniques including Western blotting, co-immunoprecipitation, and mammalian two-hybrid assays.
  • Investigated the role of retinoid X receptor alpha (RXRalpha) phosphorylation through site-directed mutagenesis.

Main Results:

  • 1,25(OH)(2)D(3) treatment induced growth arrest and gene expression, but this response was blunted in RWPE2 cells with elevated MAPK signaling.
  • MAPK inhibition restored vitamin D transcriptional responses in RWPE2 cells, while MAPK activation impaired these responses in RWPE1 cells.
  • MAPK activation reduced the interaction between RXRalpha and steroid receptor co-activator-1 (SRC-1).
  • Mutating phosphorylation sites (S32A, T82A) in the RXRalpha AF-1 domain restored 1,25(OH)(2)D(3)-mediated transactivation in RWPE2 cells.

Conclusions:

  • Prolonged MAPK activation significantly impairs 1,25(OH)(2)D(3)-mediated transcription in prostate epithelial cells.
  • This impairment is partly due to MAPK-induced phosphorylation of RXRalpha at critical sites within the AF-1 domain.
  • Disrupted RXRalpha-co-activator interaction, specifically with SRC-1, contributes to the reduced vitamin D transcriptional activity.
  • These findings highlight a potential therapeutic target for enhancing vitamin D efficacy in prostate cancer treatment.

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