Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor.
Animals
Caco-2 Cells
Calcimimetic Agents
/ pharmacology
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Colorectal Neoplasms
/ drug therapy
Gene Expression Regulation, Neoplastic
/ drug effects
Heterografts
Humans
Interleukin-23 Subunit p19
/ genetics
Interleukin-8
/ genetics
Mice
Phenethylamines
/ pharmacology
Propylamines
/ pharmacology
Receptors, Calcium-Sensing
/ genetics
Receptors, G-Protein-Coupled
/ genetics
Calcimimetic
Calcium-sensing receptor
Colorectal cancer
Inflammation
Intestine
Journal
Biochimica et biophysica acta. Molecular cell research
ISSN: 1879-2596
Titre abrégé: Biochim Biophys Acta Mol Cell Res
Pays: Netherlands
ID NLM: 101731731
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
23
03
2020
revised:
21
08
2020
accepted:
25
08
2020
pubmed:
31
8
2020
medline:
9
1
2021
entrez:
31
8
2020
Statut:
ppublish
Résumé
The calcium-sensing receptor (CaSR) is a ubiquitously expressed multifunctional G protein-coupled receptor. Several studies reported that the CaSR plays an anti-inflammatory and anti-tumorigenic role in the intestine, and that it is down-regulated during colorectal carcinogenesis. We hypothesized that positive allosteric CaSR modulators (type II calcimimetics) selectively targeting the intestinal cells could be used for the treatment of intestinal pathologies. Therefore, the aim of this study was to determine the effect of pharmacological stimulation of CaSR on gene expression in vitro and on tumor growth in vivo. We stably transduced two colon cancer cell lines (HT29 and Caco2) with lentiviral vectors containing either the CaSR fused to GFP or GFP only. Using RNA sequencing, RT-qPCR experiments and ELISA, we determined that CaSR over-expression itself had generally little effect on gene expression in these cells. However, treatment with 1 μM of the calcimimetic NPS R-568 increased the expression of pro-inflammatory factors such as IL-23α and IL-8 and reduced the transcription of various differentiation markers in the cells over-expressing the CaSR. In vivo, neither the presence of the CaSR nor p.o. treatment of the animals with the calcimimetic cinacalcet affected tumor growth, tumor cell proliferation or tumor vascularization of murine HT29 xenografts. In summary, CaSR stimulation in CaSR over-expressing cells enhanced the expression of inflammatory markers in vitro, but was not able to repress colorectal cancer tumorigenicity in vivo. These findings suggest potential pro-inflammatory effects of the CaSR and type II calcimimetics in the intestine.
Identifiants
pubmed: 32861746
pii: S0167-4889(20)30194-4
doi: 10.1016/j.bbamcr.2020.118836
pii:
doi:
Substances chimiques
Calcimimetic Agents
0
IL23A protein, human
0
Interleukin-23 Subunit p19
0
Interleukin-8
0
N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
0
Phenethylamines
0
Propylamines
0
Receptors, Calcium-Sensing
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
118836Subventions
Organisme : Austrian Science Fund FWF
ID : P 29948
Pays : Austria
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.