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Antiproliferative responses to two human colon cancer cell lines to vitamin D3 are differently modified by
K F Kane1, M J Langman, G R Williams
1Department of Medicine, Queen Elizabeth Hospital, University of Birmingham, Edgbaston, United Kingdom.
Abstract:
1 alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] exerts antiproliferative actions in colorectal cancer, but their underlying molecular mechanisms have not been determined. 1,25(OH)2D3 regulates target gene transcription via a specific nuclear vitamin D receptor (VDR), which mediates hormone action preferentially as a heterodimer with 9-cis-retinoic acid receptors (RXRs). We investigated the actions of 1,25(OH)2D3 and 9-cis-retinoic acid (RA) in two human colon cancer cell lines, HT-29 and Caco-2. Both expressed mRNAs encoding VDR, RXR alpha, and RXR gamma, and VDR was regulated posttranscriptionally in Caco-2 cells. There was an antiproliferative response of both cell lines to 1,25(OH)2D3. 9-cis-RA exerted antiproliferative effects on Caco-2 cells but blocked 1,25(OH)2D3 actions in HT-29 cells. The 1,25(OH)2D3-responsive gene 25-hydroxyvitamin D3 24-hydroxylase was induced in both cell lines b 1,25(OH)2D3 but in only HT-29 cells by 9-cis-RA. 1,25(OH)2D3 and 9-cis-RA cotreatment enhanced 24-hydroxylase expression in HT-29 cells only. The 24-hydroxylase enzyme is known to result in catabolism of 1,25(OH)2D3 and attenuation of its actions. Increased 24-hydroxylase activity in HT-29 cells, but not in Caco-2 cells, in response to 9-cis-RA may account for some of the complex cell-specific responses demonstrated in these studies.
Insights
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits colorectal cancer cell growth. Retinoic acid (RA) has complex, cell-specific effects on 1,25(OH)2D3 action, influencing vitamin D receptor (VDR) activity and cancer progression.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exhibits antiproliferative effects in colorectal cancer.
- The molecular mechanisms underlying these actions, particularly the role of the vitamin D receptor (VDR) and its heterodimerization with 9-cis-retinoic acid receptors (RXRs), are not fully elucidated.
Purpose of the Study:
- To investigate the distinct and combined effects of 1,25(OH)2D3 and 9-cis-retinoic acid (RA) on human colorectal cancer cell lines (HT-29 and Caco-2).
- To explore the molecular mechanisms, including VDR and RXR expression and the regulation of the 25-hydroxyvitamin D3 24-hydroxylase gene, in response to these compounds.
Main Methods:
- Analysis of VDR, RXR alpha, and RXR gamma mRNA expression in HT-29 and Caco-2 cells.
- Assessment of the antiproliferative effects of 1,25(OH)2D3 and 9-cis-RA on these cell lines.
- Quantification of 25-hydroxyvitamin D3 24-hydroxylase gene induction by 1,25(OH)2D3 and 9-cis-RA, individually and in combination.
Main Results:
- Both HT-29 and Caco-2 cells expressed VDR, RXR alpha, and RXR gamma; VDR expression was posttranscriptionally regulated in Caco-2 cells.
- 1,25(OH)2D3 demonstrated antiproliferative effects on both cell lines.
- 9-cis-RA inhibited Caco-2 cell proliferation but antagonized 1,25(OH)2D3's effects in HT-29 cells.
- The 1,25(OH)2D3-responsive gene 24-hydroxylase was induced by 1,25(OH)2D3 in both cell lines and by 9-cis-RA only in HT-29 cells.
- Cotreatment with 1,25(OH)2D3 and 9-cis-RA enhanced 24-hydroxylase expression exclusively in HT-29 cells.
Conclusions:
- The antiproliferative actions of 1,25(OH)2D3 in colorectal cancer are modulated in a cell-specific manner by 9-cis-RA.
- Differential induction of 24-hydroxylase activity by 9-cis-RA in HT-29 versus Caco-2 cells may explain the observed complex, cell-specific responses to vitamin D and RA.
- These findings highlight the intricate interplay between vitamin D and retinoid signaling pathways in colorectal cancer.