title: The calcium-sensing receptor: A promising target for prevention of colorectal cancer.
abstract: The inverse correlation between dietary calcium intake and the risk of colorectal cancer (CRC) is well known, but poorly understood. Expression of the calcium-sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is downregulated in CRC leading us to hypothesize that the CaSR has tumor suppressive roles in the colon. The aim of this study was to understand whether restoration of CaSR expression could reduce the malignant phenotype in CRC. In human colorectal tumors, expression of the CaSR negatively correlated with proliferation markers whereas loss of CaSR correlated with poor tumor differentiation and reduced apoptotic potential. In vivo, dearth of CaSR significantly increased expression of proliferation markers and decreased levels of differentiation and apoptotic markers in the colons of CaSR/PTH double knock-out mice confirming the tumor suppressive functions of CaSR. In vitro CRC cells stably overexpressing wild-type CaSR showed significant reduction in proliferation, as well as increased differentiation and apoptotic potential. The positive allosteric modulator of CaSR, NPS R-568 further enhanced these effects, whereas treatment with the negative allosteric modulator, NPS 2143 inhibited these functions. Interestingly, the dominant-negative mutant (R185Q) was able to abrogate these effects. Our results demonstrate a critical tumor suppressive role of CaSR in the colon. Restoration of CaSR expression and function is linked to regulation of the balance between proliferation, differentiation, and apoptosis and provides a rationale for novel strategies in CRC therapy.
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: Maximilian
authors.initials: M
authors.lastname: Prinz-Wohlgenannt
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: Julia
authors.initials: J
authors.lastname: Höbaus
authors.affiliation: INSERM U1088, University of Picardie Jules Verne, Amiens, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Boudot
authors.affiliation: INSERM U1088, University of Picardie Jules Verne, Amiens, France.
authors.forename: Romuald
authors.initials: R
authors.lastname: Mentaverri
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Brown
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: D019943:Amino Acid Substitution; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009281:Naphthalenes / Q000494:pharmacology; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; C095550:CASR protein, human; C577923:CASR protein, mouse; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins
keywords: Calcilytic; Calcimimetic; Calcium; Calcium-sensing receptor; Colon; Colorectal cancer; Tumor suppressor