Dissociation of growth arrest and CYP24 induction by VDR ligands in mammary tumor cells.
Murine mammary tumor cells with differential vitamin D receptor (VDR) expression were used to study the mechanisms of growth inhibition by vitamin D steroids. In VDR-expressing WT145 cells, 1,25D and its synthetic analog EB1089 induce growth arrest and transcriptionally upregulate the well-characterized VDR target gene CYP24. 1,25D also induces apoptosis in WT145 cells through activation of initiator and executioner caspases and the calcium-dependent protease calpain. We also demonstrate that WT145 cells express CYP27B1, the enzyme that converts 25-hydroxyvitamin D(3) (25D) to 1,25D, and that 25D inhibits growth of these cells but does not trigger apoptosis or induce CYP24 expression. Comparative studies were conducted in KO240 cells, which were derived from VDR knockout mice and found to retain expression of CYP27B1. KO240 cells were not growth inhibited nor rendered apoptotic by any of the tested vitamin D compounds. These data conclusively demonstrate that VDR mediates the anti-proliferative and pro-apoptotic effects of vitamin D metabolites and analogs, but that the potency of a vitamin D compound to induce the VDR target gene CYP24 does not accurately predict its potency in mediating growth regulation.
Valrance
Meggan E
ME
Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Brunet
Andrea H
AH
Acosta
Anna
A
Welsh
Joellen
J
D000818:Animals; D002112:Calcifediol / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D017930:Genes, Reporter; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014807:Vitamin D / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
D008024:Ligands; D018167:Receptors, Calcitriol; D014807:Vitamin D; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002112:Calcifediol