Sensitivity to growth suppression by 1alpha,25-dihydroxyvitamin D(3) among MCF-7 clones correlates with Vitamin D
Simon Skjøde Jensen1, Mogens Winkel Madsen, Jiri Lukas
1Department of Biochemistry, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark. simon@kemi.dtu.dk
Abstract:
The antiproliferative effect of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) has been studied for a decade in diverse model systems, but the signalling pathways linking 1alpha,25(OH)(2)D(3) to cell cycle arrest remains unclear. In our attempt to establish a model system which would allow further identification of important players in the process of the 1alpha,25(OH)(2)D(3) imposed cell cycle arrest, we have isolated derivatives of the human breast cancer cell line MCF-7 and chosen two nearly 1alpha,25(OH)(2)D(3) resistant and two hypersensitive sub-clones. Investigation of cell cycle proteins regulated by 1alpha,25(OH)(2)D(3) in these clones indicates that activation of one component/pathway is responsible for the linkage between 1alpha,25(OH)(2)D(3) and growth arrest. Protein levels of the Vitamin D receptor (VDR) were elevated in sensitive cells upon 1alpha,25(OH)(2)D(3) treatment, whereas resistant clones were unable to induce VDR upon 1alpha,25(OH)(2)D(3) treatment. Our data show that VDR protein levels and the ability of a cell to induce VDR upon 1alpha,25(OH)(2)D(3) treatment correlate with the antiproliferative effects of 1alpha,25(OH)(2)D(3), and suggest that the level of VDR in cancer cells might serve as a prognostic marker for treatment of cancer with 1alpha,25(OH)(2)D(3) analogues.
Insights
1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) antiproliferative effects are linked to Vitamin D Receptor (VDR) levels. Higher VDR induction in cancer cells correlates with better response to 1alpha,25(OH)(2)D(3) treatment.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- The antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) are well-documented but the underlying signaling pathways remain elusive.
- Understanding the molecular mechanisms of 1alpha,25(OH)(2)D(3) action is crucial for its therapeutic application in cancer.
Purpose of the Study:
- To investigate the role of Vitamin D Receptor (VDR) in mediating the antiproliferative effects of 1alpha,25(OH)(2)D(3) in human breast cancer cells.
- To establish a model system for identifying key players in 1alpha,25(OH)(2)D(3)-induced cell cycle arrest.
Main Methods:
- Isolation and characterization of 1alpha,25(OH)(2)D(3) resistant and hypersensitive sub-clones of the MCF-7 human breast cancer cell line.
- Analysis of cell cycle protein regulation and VDR protein levels in response to 1alpha,25(OH)(2)D(3) treatment.
Main Results:
- VDR protein levels were significantly elevated in 1alpha,25(OH)(2)D(3)-sensitive cells upon treatment.
- Resistant clones demonstrated an inability to induce VDR expression following 1alpha,25(OH)(2)D(3) exposure.
- A strong correlation was observed between VDR protein levels, VDR induction capacity, and the antiproliferative response to 1alpha,25(OH)(2)D(3).
Conclusions:
- The level of VDR expression and the cell's ability to induce VDR are critical determinants of sensitivity to 1alpha,25(OH)(2)D(3)'s antiproliferative effects.
- VDR levels in cancer cells may serve as a predictive biomarker for the efficacy of 1alpha,25(OH)(2)D(3) analogue therapy in cancer treatment.
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