title: Active vitamin D potentiates the anti-neoplastic effects of calcium in the colon: A cross talk through the calcium-sensing receptor.
abstract: Epidemiological studies suggest an inverse correlation between dietary calcium (Ca(2+)) and vitamin D intake and the risk of colorectal cancer (CRC). It has been shown in vitro that the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-D3) can upregulate expression of the calcium-sensing receptor (CaSR). In the colon, CaSR has been suggested to regulate proliferation of colonocytes. However, during tumorigenesis colonic CaSR expression is downregulated and we hypothesized that the loss of CaSR could influence the anti-tumorigenic effects of Ca(2+) and vitamin D. Our aim was to assess the impact of CaSR expression and function on the anti-neoplastic effects of 1,25-D3 in colon cancer cell lines. We demonstrated that in the healthy colon of mice, high vitamin D diet (2500 IU/kg diet) increased expression of differentiation and apoptosis markers, decreased expression of proliferation markers and significantly upregulated CaSR mRNA expression, compared with low vitamin D diet (100 IU/kg diet). To determine the role of CaSR in this process, we transfected Caco2-15 and HT29 CRC cells with wild type CaSR (CaSR-WT) or a dominant negative CaSR mutant (CaSR-DN) and treated them with 1,25-D3 alone, or in combination with CaSR activators (Ca(2+) and NPS R-568). 1,25-D3 enhanced the anti-proliferative effects of Ca(2+) and induced differentiation and apoptosis only in cells with a functional CaSR, which were further enhanced in the presence of NPS R-568, a positive allosteric modulator of CaSR. The mutant CaSR inhibited the anti-tumorigenic effects of 1,25-D3 suggesting that the anti-neoplastic effects of 1,25-D3 are, at least in part, mediated by the CaSR. Taken together, our data provides molecular evidence to support the epidemiological observation that both, vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Höbaus
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Samawansha
authors.initials: S
authors.lastname: Tennakoon
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Prinz-Wohlgenannt
authors.affiliation: Safety Assessment, AstraZeneca, Macclesfield, UK.
authors.forename: João
authors.initials: J
authors.lastname: Graça
authors.affiliation: Safety Assessment, AstraZeneca, Macclesfield, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Price
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Research Platform 'Translational Cancer Therapy Research', Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Research Platform 'Translational Cancer Therapy Research', Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Sabina
authors.initials: S
authors.lastname: Baumgartner-Parzer
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria. Electronic address: enikoe.kallay@meduniwien.ac.at.
authors.forename: Enikö
authors.initials: E
authors.lastname: Kállay
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019587:Dietary Supplements; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; C577923:CASR protein, mouse; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002118:Calcium
keywords: Calcimimetic; Calcium; Calcium-sensing receptor; Chemoprevention; Colon cancer; Vitamin D