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.

Expression profiling of colorectal cancer cells reveals inhibition of DNA replication licensing by extracellular calcium

“…In order to test whether the CaSR mediates also the effect of [Ca 2+ ] o on replication licensing we used the HT29 cell line stably transfected either with the full length CaSR (HT29 CaSR ) or with an empty vector (HT29 Emp ). In contrast to Caco-2 cells, parental HT29 cells are not responsive to the antiproliferative effect of [Ca 2+ ] o [33] and express undetectable levels of CaSR [34]. The HT29 CaSR cells overexpressing the CaSR, expressed significantly lower levels of CDT1, CDC6, CDC45, and MCM2 compared with the HT29 Emp controls (Fig.…”

Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression

“…However, in the context of colorectal cancer and parathyroid tumors, higher CaSR expression has been observed to be protective (26). In colorectal cancer, activation of CaSR promotes E-cadherin expression and down-regulates the Wnt/␤-catenin pathway (27,28).…”

Intracellular Ca 2+ oscillations generated via the extracellular Ca 2+ -sensing receptor (CaSR) in response to extracellular Ca 2+ or l -phenylalanine: Impact of the highly conservative mutation Ser170Thr

“…Interestingly, subsequent studies demonstrated that the CaSR recognizes other ligands and is expressed in many other tissues and organs, including the gastrointestinal tract, brain, pituitary, thyroid, skin, breast, pancreas, lung, bone, and heart [2], suggesting that this receptor plays additional, yet less well defined, physiological roles in the regulation of normal and abnormal cell function [3,4,5,6]. Indeed, recent evidence indicates that the CaSR is implicated in the negative control of colon cell proliferation [7] and cancer [8], nutrient sensing [4], epithelial transport [9], inflammation [10], bone turnover [11] and stem cell differentiation [6]. Thus, the signaling mechanisms triggered via CaSR activation are attracting intense attention.…”