Nifedipine synergizes with calcium in activating the calcium sensing receptor, suppressing the expression of thymidylate synthase and survivin and promoting sensitivity to fluorouracil in human colon carcinoma cells

Abstract

We have previously reported that activation of the G protein coupled calcium-sensing receptor (CaSR) by extracellular Ca(2+) down-modulates the expression of thymidylate synthase (TS) and survivin and promotes sensitivity to fluorouracil in human colon carcinoma cells. Here, we report for the first time that the cardiac drug nifedipine acted synergistically with Ca(2+) in CaSR activation and in the induction of intracellular Ca(2+). Nifedipine in combination with Ca(2+) significantly down-modulated the expression of TS and survivin and promoted sensitivity to 5-FU above and beyond the level achievable with Ca(2+) alone. Nifedipine by itself, however, had no effect on the suppression of TS or survivin or sensitivity to 5-FU. The action of Ca(2+) or in combination with nifedipine was entirely CaSR dependent as the aforementioned effects did not occur in CaSR knocked down cells. siRNAs targeting TS or survivin or both could mimic the effect of CaSR activation in promoting sensitivity to 5-FU. We conclude that nifedipine acts in synergy with Ca(2+) in activating CaSR and in promoting sensitivity to 5-FU by down modulating the expression of TS and survivin. G-protein coupled CaSR has the potential of serving as a target for improving therapeutic outcome in colon cancer.

Significance of calcium-sensing receptor expression in gastric cancer

“…These results coincide with those of a previous study obtained using colon, breast, and renal cell carcinomas [9,11,13,14,17,18]. Loss of CaSR expression activates a myriad of stem cell-like molecular features that drive and sustain the carcinomas and drugresistant phenotypes of colon cancer [10,19]. CaSR might regulate the differentiation of colonic epithelial cells.…”

Growth Control in Colon Epithelial Cells: Gadolinium Enhances Calcium-Mediated Growth Regulation

“…Our previous studies have demonstrated that calcium-induced growth suppression depends on the activation of CaSR [14, 15, 17]. This is associated with differentiation and depends on a transient rise in the level of intracellular calcium [35]. Based on these past data, we hypothesized that exposure of the colonic epithelial cells to gadolinium in conjunction with calcium would induce a rise in intracellular calcium over that seen with calcium alone.…”

Isolation and characterization of calcium sensing receptor null cells: A highly malignant and drug resistant phenotype of colon cancer

“…CaSR promotes the expression of the tumor suppressor E‐cadherin 12–14. It up‐regulates the expression of the growth‐inhibitory and differentiation related p21/Waf1 cell cycle check point protein; up‐regulates the expression of γ‐catenin and p27; suppresses the malignancy associated β‐catenin/Wnt, c‐myc and cyclin D1 pathways12–15 and suppresses the expression of thymidylate synthase (TS) and survivin 16, 17, 19. Some of these pathways have been validated by immunohistochemical analysis of histological sections of normal human colon and colon tumor 15.…”

“…A high level of survivin expression blocks the ease in which cell death occur in response to treatment with anticancer drugs and a high level of survivin expression is associated with cytotoxic drug resistance in many types of cancer 26–28. CaSR suppresses the expression of both TS and survivin and promotes a dramatic increase in the cytotoxic response to 5‐FU 16, 17, 19…”