Clonal differences in expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase, of 25-hydroxyvitamin D(3)-24-hydroxylase, and of the vitamin D receptor in human colon carcinoma cells: effects of epidermal growth factor and 1alpha,25-dihydroxyvitamin D(3)

Exp Cell Res. 2002 Jun 10;276(2):320-7. doi: 10.1006/excr.2002.5528.

Abstract

Human colon carcinoma cells express 25-hydroxyvitamin D(3)-1alpha-hydroxylase (CYP27B1) and thus produce the vitamin D receptor (VDR) ligand 1alpha,25-dihydroxyvitamin D(3) (1,25-D3), which can be metabolized by 25-hydroxyvitamin D(3)-24-hydroxylase (CYP24). Expression of VDR, CYP27B1, and CYP24 determines the efficacy of the antimitotic action of 1,25-D3 and is distinctly related to the degree of differentiation of cancerous lesions. In the present study we addressed the question of whether the effects of epidermal growth factor (EGF) and of 1,25-D3 on VDR, CYP27B1, and CYP24 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation. We were able to show that slowly dividing, highly differentiated Caco-2/15 cells responded in a dose-dependent manner to both EGF and 1,25-D3 by up-regulation of VDR and CYP27B1 expression, whereas in highly proliferative, less differentiated cell lines, such as Caco-2/AQ and COGA-1A and -1E, negative regulation was observed. CYP24 mRNA was inducible in all clones by 1,25-D3 but not by EGF. From the observed clonal differences in the regulatory effects of EGF and 1,25-D3 on VDR and CYP27B1 gene expression we suggest that VDR-mediated growth inhibition by 1,25-D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by EGF.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / drug effects
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism*
  • Calcitriol / metabolism
  • Calcitriol / pharmacology
  • Carcinoma / enzymology*
  • Carcinoma / physiopathology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Clone Cells / drug effects
  • Clone Cells / metabolism
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / physiopathology
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Steroid Hydroxylases / drug effects
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism*
  • Tumor Cells, Cultured
  • Vitamin D3 24-Hydroxylase

Substances

  • RNA, Messenger
  • Receptors, Calcitriol
  • Epidermal Growth Factor
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Calcitriol