Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines

S. H. Zhuang, G. G. Schwartz, D. Cameron, Kerry L Burnstein

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Prostate cancer cell lines exhibit variable growth suppression by the hormonal form of vitamin D3, 1,25-Dihydroxyvitamin D3 [1,25 (OH)2D] (1,25 D3). To understand the molecular basis for this differential sensitivity to 1,25 D3, we compared growth response to 1,25 D3, vitamin D receptor (VDR) content and VDR transcriptional activity in four well-characterized human prostate cancer cell lines: LNCaP, DU145, PC-3 and ALVA-31. In PC-3 and DU145 cells, relative lack of growth inhibition by 1,25 D3 (< 10% inhibition) correlates with very low levels of VDR (9-15 fmol/mg protein) compared to classical vitamin D3 target tissues (~ 75-200 fmol/mg protein). Transfection of DU145 and PC-3 cells with a VDR cDNA expression vector is sufficient to establish growth sensitivity to 1,25 D3, suggesting that low VDR levels are responsible for the failure of these cell lines to respond to 1,25 D3. LNCaP cells are highly sensitive to growth inhibition by 1,25 D3 (~ 55% inhibition) and contain ~ 2-3-fold more VDR (25 fmol/mg) than the relatively 1,25 D3-insensitive PC-3 and DU145 cell lines. However, ALVA-31 cells display less than 20% growth inhibition to 1,25 D3 although they contain the highest levels of VDR (45 fmol/mg) of the four cell lines. Thus, sensitivity to growth inhibition by 1,25 D3 does not correlate with VDR content in ALVA-31 and LNCaP cells. This lack of correlation between VDR density and growth responses to 1,25 D3 led us to investigate VDR-mediated gene transcription in these cell lines. We employed two different naturally-occurring vitamin D response elements (VDREs) linked to a reporter gene. Reporter gene activation by 1,25 D3 correlated well with VDR content in all four cell lines. Therefore, compared to LNCaP cells, decreased sensitivity of ALVA-31 to growth inhibition by 1,25 D3 is not due to a decrease in the general transcriptional activity of VDR. We conclude that growth inhibition by 1,25 D3 in prostate cancer cells requires VDR but that this response is modulated by non-receptor factors that are cell line-specific.

Original languageEnglish
Pages (from-to)83-90
Number of pages8
JournalMolecular and Cellular Endocrinology
Volume126
Issue number1
DOIs
StatePublished - Jan 3 1997

Fingerprint

Calcitriol Receptors
Vitamin D
Prostatic Neoplasms
Cells
Cell Line
Growth
Genes
Cholecalciferol
Reporter Genes
Vitamin D Response Element
Calcitriol
Transcription
Transcriptional Activation
Transfection
Proteins

Keywords

  • Calcitriol
  • Cellular proliferation
  • Prostate cancer cell lines
  • Reporter gene assay
  • Vitamin D
  • Vitamin D receptors

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines. / Zhuang, S. H.; Schwartz, G. G.; Cameron, D.; Burnstein, Kerry L.

In: Molecular and Cellular Endocrinology, Vol. 126, No. 1, 03.01.1997, p. 83-90.

Research output: Contribution to journalArticle

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abstract = "Prostate cancer cell lines exhibit variable growth suppression by the hormonal form of vitamin D3, 1,25-Dihydroxyvitamin D3 [1,25 (OH)2D] (1,25 D3). To understand the molecular basis for this differential sensitivity to 1,25 D3, we compared growth response to 1,25 D3, vitamin D receptor (VDR) content and VDR transcriptional activity in four well-characterized human prostate cancer cell lines: LNCaP, DU145, PC-3 and ALVA-31. In PC-3 and DU145 cells, relative lack of growth inhibition by 1,25 D3 (< 10{\%} inhibition) correlates with very low levels of VDR (9-15 fmol/mg protein) compared to classical vitamin D3 target tissues (~ 75-200 fmol/mg protein). Transfection of DU145 and PC-3 cells with a VDR cDNA expression vector is sufficient to establish growth sensitivity to 1,25 D3, suggesting that low VDR levels are responsible for the failure of these cell lines to respond to 1,25 D3. LNCaP cells are highly sensitive to growth inhibition by 1,25 D3 (~ 55{\%} inhibition) and contain ~ 2-3-fold more VDR (25 fmol/mg) than the relatively 1,25 D3-insensitive PC-3 and DU145 cell lines. However, ALVA-31 cells display less than 20{\%} growth inhibition to 1,25 D3 although they contain the highest levels of VDR (45 fmol/mg) of the four cell lines. Thus, sensitivity to growth inhibition by 1,25 D3 does not correlate with VDR content in ALVA-31 and LNCaP cells. This lack of correlation between VDR density and growth responses to 1,25 D3 led us to investigate VDR-mediated gene transcription in these cell lines. We employed two different naturally-occurring vitamin D response elements (VDREs) linked to a reporter gene. Reporter gene activation by 1,25 D3 correlated well with VDR content in all four cell lines. Therefore, compared to LNCaP cells, decreased sensitivity of ALVA-31 to growth inhibition by 1,25 D3 is not due to a decrease in the general transcriptional activity of VDR. We conclude that growth inhibition by 1,25 D3 in prostate cancer cells requires VDR but that this response is modulated by non-receptor factors that are cell line-specific.",
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