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Molecular mechanism of cell regulatory properties of vitamin D analogues in human cancer cell lines
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent modulator of the induction of differentiation and inhibition of cell growth in both malignant and normal cells. Vitamin D and its analogues exert their effects through a transcription factor, the nuclear vitamin D receptor (VDR). The VDR can form a homodimer or heterodimers with other nuclear receptors. Its main heterodimer partner is the retinoid X receptor (RXR), which is the nuclear receptor for 9-cis retinoic acid. VDR-RXR heterodimers bind to vitamin D response elements (VDREs) that are formed by directly repeated hexameric core binding motifs spaced by 3 nucleotides (DR3-type VDREs), or by inverted palindromes spaced by 9 nucleotides (IP9-type VDREs).

This study addressed the cell regulatory properties of vitamin D analogues in human cancer cell lines, mainly in the breast cancer cell line MCF-7 and in the melanoma cell lines WM1341 and MeWo, It was found that of 1α,25-dihydroxyvitamin D3 and its analogues, EB1089 and KH1230 anti-proliferative effects are not mediated by repression of AP-1-mediated gene activity, which has beenobserved for the retinoids. Further observations seen in these studies were that EB1089 and ZK161422, two potent and completely different vitamin D analogues, were capable of demonstrating a promoter selectivity for an IP9-type VDRE. Interestingly, CB1093 the most potent vitamin D analogue in these studies showed a promoter selectivity for a DR3-type VDRE. Additional studies with a synthetic retinoid, CD437 and 1α,25-dihydroxyvitamin D3 resulted in a synergistic enhancement of apoptosis in WIG1341 melanoma cells. These studies demonstrated that the vitamin D analogues have potential as therapeutic agents in breast cancer and melanoma.

Two novel vitamin D-regulated genes, the cyclin C and p19INK4D, involved in cell proliferation were identified by an mRNA differential display reverse transcriptase-polymerase chain reaction (DDRT-PCR) approach. Up-regulation at both mRNA and protein levels for cyclin C and p19INK4D were successfully shown in MCF-7 cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , 52 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 786
Keyword [en]
Medical sciences, vitamin D analogues, retinoids, cancer cell lines, promoter selectivity, cell regulatory properties
Keyword [sv]
MEDICIN OCH VÅRD
National Category
Medical and Health Sciences
Research subject
Dermatology and Venerology
Identifiers
URN: urn:nbn:se:uu:diva-220ISBN: 91-554-4301-X (print)OAI: oai:DiVA.org:uu-220DiVA: diva2:161822
Public defence
1998-11-09, Rosensalen, Uppsala University Hospital, Entrance 95, Uppsala, 09:15
Available from: 1998-10-19 Created: 1998-10-19Bibliographically approved

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