Calcium and calcium sensing receptor modulates the expression of thymidylate synthase, NAD(P)H:quinone oxidoreductase 1 and survivin in human colon carcinoma cells: Promotion of cytotoxic response to mitomycin C and fluorouracil

Abstract

Ca 2+ and the cell-surface calcium sensing receptor (CaSR) constitute a novel and robust ligand/ receptor system in regulating the proliferation and differentiation of colonic epithelial cells. Here we show that activation of CaSR by extracellular Ca 2+ (or CaSR agonists) enhanced the sensitivity of human colon carcinoma cells to mitomycin C (MMC) and fluorouracil (5-FU). Activation of CaSR up-regulated the expression of MMC activating enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO-1) and down-regulated the expression of 5-FU target, thymidylate synthase (TS) and the anti-apoptotic protein survivin. Cells that were resistant to drugs expressed little or no CaSR but abundant amount of survivin. Disruption of CaSR expression by shRNA targeting the CaSR abrogated these modulating effects of CaSR activation on the expression of NQO1, TS, survivin and cytotoxic response to drugs. It is concluded that activation of CaSR can enhance colon cancer cell sensitivity to MMC and 5-FU and can modulate the expression of molecules involved in the cellular responses to these cytotoxic drugs.

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

“…15 Liu et al 15 reported that functional CASR is necessary for tumor suppressive function of vitamin D and that this function is abrogated by knocking down CASR expression. Therefore, from the viewpoint of chemotherapy and/ or chemoprevention using Ca 2 þ and/or vitamin D, the results obtained in this study are important.…”

“…11,12,15 To assess the effect of Ca 2 þ on the cytotoxic response to drugs, the medium of cells was replenished with a medium containing physiological concentrations of Ca 2 þ (1.4 mM) and 5-FU (15 mM). The medium of a parallel set of cultures was replenished with a medium only containing 5-FU without the addition of exogenous Ca 2 þ .…”

“…CASR reportedly controls proliferation and differentiation in the human colonic epithelium and colon carcinoma cells. [10][11][12][13][14][15][16][17][18] Increased thymidylate synthase expression is one the most important mechanisms underlying the resistance to 5-fluorouracil (FU) in colorectal cancer. 19,20 Interestingly, activation of CASR reportedly downregulates the expression of thymidylate synthase and survivin, and upregulates cellular sensitivity to 5-FU in human colorectal cancer cell lines.…”

“…19,20 Interestingly, activation of CASR reportedly downregulates the expression of thymidylate synthase and survivin, and upregulates cellular sensitivity to 5-FU in human colorectal cancer cell lines. 15 Moreover, it has been reported that vitamin D mediates its action in human colorectal cancer cells in a CASR-dependent manner and downregulates malignant cell behavior. 21 Ion transport systems are often altered in human cancer.…”

Effects of potential calcium sensing receptor inducers on promoting chemosensitivity of human colon carcinoma cells

“…In colon cancer, welldifferentiated carcinoma cells express observable levels of CaSR, whereas undifferentiated carcinoma cells have little or no CaSR expression (7-10). Since undifferentiated status is one of the mechanisms underlying drug resistance, we have hypothesized in our previous studies that CaSR is involved in chemosensitivity of human colon carcinoma cells and found that activation or induction of CaSR in the cells significantly promoted the sensitivity of the cells to anticancer drug treatment (11,12).The human CaSR gene has two promoters (P1 and P2) and each promoter has a transcriptional start site (4,13-15). Both promoters contain the vitamin D (VD) response element (VDRE), which is recognized and bound by the complex of VD receptor (VDR) activated and bound by VD (15).…”