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.

Keywords: CaSR; VDR; VDRE; calcium; colorectal cancer; vitamin D.

Figure 1

Impact of the inactivating CaSR mutation on the apoptotic effect of 1,25D₃ and NPS R-568 in the colon cancer cell lines Caco2-15 (A) and HT29 (B), stably transfected with wild type (CaSR-WT) or the dominant negative R185Q mutant (CaSR-DN). Cells transfected with and empty vector (EMP) were used as controls. One week post confluence, the cells were treated with 1,25D₃ (1 nM), NPS R-568 (1 μM) or a combination of 1,25D₃ and NPS R-568 for 48 h. Apoptosis was assessed by measuring caspase3/7 activity. Bars represent mean ± SEM. Statistical significance was calculated using two-way ANOVA followed by Tukey's correction. ^*p < 0.05, ^**p < 0.01, ^***p < 0.001. Modified from Aggarwal et al. (2016).

Figure 2

Interactions between the vitamin D system and the CaSR. Ca/CaSR and the 1,25D₃/VDR cross talk to protect colonic epithelial cells from malignant transformation. 1,25D₃ is able to up regulate expression of both, CaSR and Cyp24a1. The wild type CaSR has a tumor suppressive role in the colon promoting (blue arrows) differentiation and apoptosis and suppressing (red arrows) proliferation and EMT and potentiates the tumor preventive effects of 1,25D₃. The presence of a DN mutant CaSR abrogates the tumor preventive effects of both Ca and 1,25D₃.