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  • The calcium-sensing receptor: A promising target for prevention of colorectal cancer.

The calcium-sensing receptor: A promising target for prevention of colorectal cancer.

Biochimica et biophysica acta (2015-02-24)
Abhishek Aggarwal, Maximilian Prinz-Wohlgenannt, Samawansha Tennakoon, Julia Höbaus, Cedric Boudot, Romuald Mentaverri, Edward M Brown, Sabina Baumgartner-Parzer, Enikö Kállay
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Edelfosine, ≥95% (HPLC)
Sigma-Aldrich
Sodium selenite, SAJ first grade, ≥90.0%
Sigma-Aldrich
Sodium selenite, 99%
Sigma-Aldrich
Sodium selenite, BioReagent, suitable for cell culture, ≥98%
Sigma-Aldrich
Sodium selenite, γ-irradiated, lyophilized powder, BioXtra, suitable for cell culture
Sigma-Aldrich
R-568 hydrochloride, ≥95% (HPLC)
Sigma-Aldrich
DAPI, for nucleic acid staining