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Suppression of death receptor-mediated apoptosis by 1,25-dihydroxyvitamin D3 revealed by microarray analysis

Xiaohui Zhang1, Pengfei Li, Junying Bao

  • 1Department of Pathology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.

The Journal of Biological Chemistry
|August 12, 2005
PubMed

Insights

1,25-dihydroxyvitamin D3 shows dual effects on ovarian cancer cell death, initially inhibiting apoptosis by altering death receptor expression. Manipulating these receptors can overcome this protective effect for combined therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • 1,25-dihydroxyvitamin D3 (calcitriol) is explored for ovarian cancer therapy due to its growth-inhibiting properties.
  • Understanding the molecular mechanisms of calcitriol's action is crucial for optimizing its therapeutic potential.

Purpose of the Study:

  • To investigate the molecular mechanisms by which 1,25-dihydroxyvitamin D3 affects ovarian cancer cell apoptosis.
  • To identify key genes and pathways regulated by calcitriol in ovarian cancer cells.

Main Methods:

  • Microarray analysis to profile transcriptome-wide changes induced by 1,25-dihydroxyvitamin D3.
  • Reverse transcription-PCR and Western blot to validate gene and protein expression changes.
  • RNA interference and ectopic expression to assess the role of specific death receptors.

Main Results:

  • Over 200 genes were identified as regulated by 1,25-dihydroxyvitamin D3 in ovarian cancer cells.
  • Calcitriol up-regulated TRAIL receptor 4 (decoy receptor) and down-regulated Fas (death receptor) at transcript and protein levels.
  • Pretreatment with calcitriol reduced apoptosis induced by TRAIL and Fas ligand, indicating a protective effect.

Conclusions:

  • 1,25-dihydroxyvitamin D3 exhibits a dual role in ovarian cancer cell death, potentially inhibiting apoptosis via modulation of death receptors.
  • Targeting TRAIL receptor 4 and Fas can overcome the protective effects of calcitriol, suggesting combination therapy strategies.
  • Molecular manipulation of death receptors may enable patients to benefit from combined treatments with calcitriol and death receptor ligands like TRAIL.

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