The anti-proliferative effect of vitamin D3 analogues is not mediated by inhibition of the AP-1 pathway, but may be related to promoter selectivity

Oncogene. 1995 Nov 2;11(9):1853-8.

Abstract

The hormone 1,25-dihydroxyvitamin D3 (VD) is able to induce cellular differentiation and to inhibit cellular proliferation, which provides it with an interesting therapeutic potential in cancer. However, side effects of VD on homeostasis (eg hypercalcemia) had made the need for the development of VD analogues with low calcemic effect. On the human breast cancer cell line MCF-7 we obtained with the VD analogue EB1089 an about 100-fold higher anti-proliferative effect than with VD. We found that this difference in biological activity is neither related to increased functional affinity to the VD receptor nor to repression of AP-1 activity. The physiologically most prominent complex of the VD receptor is a heterodimer with the retinoid X receptor that binds VD response elements formed two hexameric core binding motifs being arranged either as direct repeats spaced by 3 nucleotides (DR3s) or as inverted palindromes spaced by 9 nucleotides (IP9s). We observed that EB1089 stimulates transcriptional activation from IP9-type elements at clearly lower concentrations than from DR3-type elements. It is possible that IP9-type response elements play an important role in or contribute to the control of cell proliferation, so that promoter-selectivity may explain the high anti-proliferative effect of EB1089.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms
  • Calcitriol / analogs & derivatives*
  • Calcitriol / pharmacology
  • Cell Differentiation / drug effects
  • Cell Line
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kinetics
  • Macromolecular Substances
  • Molecular Sequence Data
  • Molecular Structure
  • Promoter Regions, Genetic* / drug effects
  • Receptors, Calcitriol / chemistry
  • Receptors, Calcitriol / drug effects*
  • Receptors, Calcitriol / metabolism
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / drug effects
  • Receptors, Retinoic Acid / metabolism
  • Retinoid X Receptors
  • Structure-Activity Relationship
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / drug effects
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Vitamin D / analogs & derivatives
  • Vitamin D / pharmacology*

Substances

  • 25-O-ethyl-calcitriol
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Macromolecular Substances
  • Receptors, Calcitriol
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factor AP-1
  • Transcription Factors
  • Vitamin D
  • Calcitriol
  • seocalcitol