Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer

Abstract

There is epidemiological evidence for the cancer preventive effect of dietary calcium (Ca2+) and vitamin D. This effect is strongest in colorectal cancer (CRC). The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D3), bound to its receptor, the vitamin D receptor (VDR) regulates the expression of hundreds of different genes in a cell- and tissue-specific manner. While Ca2+ acts through multiple mechanisms and pathways, some of its effects are mediated by the calcium-sensing receptor (CaSR). The joint action of Ca2+ and 1,25D3 is due to the fact that both regulate some of the main processes involved in the development of various cancers, such as proliferation, differentiation, apoptosis, migration, and inflammation. Moreover, 1,25D3, bound to VDR can induce translation of the CaSR, while the amount and activity of the CaSR affects 1,25D3 signaling. However, the complexity of the cross-talk between the CaSR and the vitamin D system goes beyond regulating similar pathways and affecting each other's expression. Our aim was to review some of the mechanisms that drive the cross-talk between the vitamin D system and the CaSR with a special focus on the interaction in CRC cells. We evaluated the molecular evidence that supports the epidemiological observation that both vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR.

Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel

“…This is consistent with previous observation that in high [Ca 2þ ] o , esophago-gastric cancer cells proliferated whereas normal cells stayed quiescent (22). Collectively, our data suggest that calcium and CaSR are tumor promoters in gastric cancer, which contrasts their roles as tumor suppressors in colorectal cancer and pancreatic cancer (3,6,7). Currently, it is unknown why the CaSR in gastric cancer has opposite roles from those in colorectal cancer and pancreatic cancer, but it is likely that: (i) the changes in CaSR expression are different in various types of tumors (enhanced expression in gastric cancer, but decreased expression in colorectal cancer and pancreatic cancer); (ii) the different downstream signaling of CaSR activation (TRPV4-mediated Ca 2þ signaling in gastric cancer, but other signaling in colorectal cancer and pancreatic cancer); (iii) even Ca 2þ signaling as shown in our study, low CaSR expression in normal gastric cells leads to low [Ca 2þ ] cyt concentration that inhibits AKT/b-catenin, but high CaSR expression in gastric cancer cells leads to high [Ca 2þ ] cyt concentration that activates AKT/b-catenin.…”

“…On day 30 after implantation of SGC-7901 cells, the mice were killed and then the xenografted tumor volumes were measured using a digital caliper. The tumor volume in mm 3 was calculated by the formula1/2 (length  width 2 ). For the experiment in which CaCl 2 was injected intravenously in mouse tail vein with serum calcium measurement, male nude mice with xenografts were randomly assigned to control group and treatment group, between them there was no significantly difference in their basal values of serum calcium (ranging from 2.20 to 2.65 mmol/L).…”

Vitamin D Receptor Signaling and Cancer

“…160 Similarly, vitamin D and calcium dietary interventions and can modulate colon crypt hyperplasia 161 and provide a rationale for how diet, inflammation, and premalignant cells could all interact and modulate cancer progression. 143,[162][163][164][165]…”

An Excess of CYP24A1, Lack of CaSR, and a Novel lncRNA Near the PTH Gene Characterize an Ectopic PTH-Producing Tumor

“…Lethal hypercalcemia in mice and humans can be induced by systemic inactivity of the CaSR gene and PTH overexpression in the parathyroid [ 39 – 41 ]. Thus, if any first hit triggers PTH production in nonparathyroid cells, a chance might exist that its expression would be reinforced via disruption of the CaSR signal transduction system [ 72 – 75 ]. The absence of CaSR in the adult parathyroid has been reported to be a possible trigger for parathyroid tumor formation [ 76 ].…”