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).
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.
Bareis
Petra
P
Department of Pathophysiology, University of Vienna Medical School, Austria.
Kállay
Enikö
E
Bischof
Martin G
MG
Bises
Giovanna
G
Hofer
Harald
H
Pötzi
Christian
C
Manhardt
Teresa
T
Bland
Rosemary
R
Cross
Heide S
HS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology; D002277:Carcinoma / Q000201:enzymology* / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000503:physiopathology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D065668:Vitamin D3 24-Hydroxylase
D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D004815:Epidermal Growth Factor; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol