Associations between vitamin D-binding protein isotypes, circulating 25(OH)D levels, and vitamin D metabolite uptake in colon cancer cells

Elizabeth A. Hibler*, Elizabeth T. Jacobs, Angelika Dampf Stone, Christine L. Sardo, Michael A. Galligan, Peter W. Jurutka

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Vitamin D metabolites have been extensively studied as cancer chemopreventive agents. Gc-globulin (GC) isotypes, based on rs7041 and rs4588 diplotypes, have varying affinities for 1α,25-dihydroxyvitamin D (1,25(OH)2D) and 25-hydroxyvitamin D (25(OH)D), which may affect circulating metabolite concentration as well as delivery at the cellular level. We evaluated associations between GC isotype and circulating vitamin D metabolite concentrations in 403 ursodeoxycholic acid (UDCA) clinical trial participants. Metabolite uptake was evaluated in human colon cancer (HCT-116) cells treated with ethanol vehicle, 1,25(OH)2D, or 25(OH)D, and with plasma from individuals with known GC isotype. Mammalian-2-hybrid and vitamin D-responsive element-based luciferase assays were used to measure the vitamin D receptor pathway activation as a marker for metabolite uptake. Regression analysis demonstrated significantly lower serum 25(OH)D concentration for clinical trial participants with 1F-2, 1S-2, or 2-2 isotypes (P < 0.01) compared with 1S-1S. Consistent with these in vivo observations, cellular data revealed that 25 (OH)D uptake varied less by GC isotype only at the higher concentration tested (P = 0.05), while 1,25 (OH)2D uptake differed markedly by GC isotype across concentration and assay (P < 0.01). The 1F-1S and 1F-2 isotypes produced the greatest reporter gene induction with 1,25(OH)2D treatment and, while activation varied less with 25(OH)D, the 2-2 isotype demonstrated increased induction at the lower concentration. These results suggest that vitamin D metabolite concentration and delivery to colon cells may vary not only by GC isotype, but also that certain isotypes may more effectively deliver 1,25(OH)2D versus 25(OH)D. Overall, these results may help identify populations at risk for cancer and potential recipients of targeted chemoprevention.

Original languageEnglish (US)
Pages (from-to)426-434
Number of pages9
JournalCancer Prevention Research
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 2014

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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