The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon

Abstract

BackgroundThe calcium sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is expressed also in tissues not directly involved in calcium homeostasis like the colon. We have previously reported that CaSR expression is down-regulated in colorectal cancer (CRC) and that loss of CaSR provides growth advantage to transformed cells. However, detailed mechanisms underlying these processes are largely unknown.Methods and resultsIn a cohort of 111 CRC patients, we found significant inverse correlation between CaSR expression and markers of epithelial-to-mesenchymal transition (EMT), a process involved in tumor development in CRC. The colon of CaSR/PTH double-knockout, as well as the intestine-specific CaSR knockout mice showed significantly increased expression of markers involved in the EMT process. In vitro, stable expression of the CaSR (HT29CaSR) gave a more epithelial-like morphology to HT29 colon cancer cells with increased levels of E-Cadherin compared with control cells (HT29EMP). The HT29CaSR cells had reduced invasive potential, which was attributed to the inhibition of the Wnt/β-catenin pathway as measured by a decrease in nuclear translocation of β-catenin and transcriptional regulation of genes like GSK-3β and Cyclin D1. Expression of a spectrum of different mesenchymal markers was significantly down-regulated in HT29CaSR cells. The CaSR was able to block upregulation of mesenchymal markers even in an EMT-inducing environment. Moreover, overexpression of the CaSR led to down-regulation of stem cell-like phenotype.ConclusionsThe results from this study demonstrate that the CaSR inhibits epithelial-to-mesenchymal transition and the acquisition of a stem cell-like phenotype in the colon of mice lacking the CaSR as well as colorectal cancer cells, identifying the CaSR as a key molecule in preventing tumor progression. Our results support the rationale to develop new strategies either preventing CaSR loss or reversing its silencing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0330-4) contains supplementary material, which is available to authorized users.

Calcium-sensing receptor in nutrient sensing: an insight into the modulation of intestinal homoeostasis

“…In mice, the conditional knocking out of CaSR reduced β-catenin phosphorylation in the colon, whereas CaSR stimulation increased phosphorylation of β-catenin in a cell line derived from normal colon mucosal epithelium. Importantly, β-catenin primarily functions in the modulation of the canonical Wnt/ β-catenin signalling pathway, which is essential to intestinal development and enhances epithelial proliferation and differentiation (36,(46)(47)(48) . Thus, CaSR activation mediates gut cell proliferation and differentiation probably via β-catenin signalling and affects intestinal development and growth.…”

Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

“…CaSR activation has been described to promote cardiac fibrosis [41]. In contrast, cinacalcet seems to reduce collagen deposition in models of kidney failure [42] and downregulation of mesenchymal markers is also associated with CaSR activation in colon cancer cell lines [43]. In MYCN-amplified xenografts, cinacalcet treatment was associated with induction of fibrosis while normal organs were not affected.…”

MCL-1 plays an oncogenic role in breast cancer by modulating chemoresistance and stemness properties by activating Wnt/β-catenin

“…When the concentration of β-catenin in the cytoplasm reaches a certain level, it can translocate to the nucleus and combine with TCF/lefs, which lead to cell proliferation, differentiation and maturation [33]. Several studies in different tumors have con rmed that the WNT/β-catenin signaling pathway mediates stem cell renewal and drug resistance by promoting translocation to the nucleus of β-catenin [34][35][36]. Our data provide evidence that MCL-1 promotes cancer stem cell characteristics and drug resistance though the WNT/βcatenin signaling pathway, which offers a novel strategy for targeted therapy in breast cancer.…”