Calcium enhances sensitivity to fluorouracil in colon carcinoma cells by modulating thymidylate synthase and survivin expression through the calcium sensing receptor Free

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Calcium and the calcium sensing receptor (CaSR) function to regulate proliferation and differentiation in human colon carcinoma cells and loss of CaSR expression is associated with malignant transformation and progression in the colon (Cancer Res., 63: 67, 2003; 65: 493, 2005). In this report, we show that CaSR positive human colon carcinoma cells were more sensitive to fluorouracil (5-FU) and were preferentially killed by 5-FU by comparison to CaSR negative cells. Extracellular Ca²⁺ (1.4 mM) enhanced the sensitivity of colon carcinoma cells to 5-FU and down-regulated the expression of thymidylate synthase (TS) and survivin. However, expression of shRNA targeting the CaSR in these cells blocked the ability of extracellular Ca²⁺ to enhance the cytotoxic response to 5-FU and to down-regulate the expression of TS and survivin. We conclude that extracellular Ca²⁺ regulates cellular sensitivity to 5-FU by modulating the expression of TS and survivin in a CaSR dependent manner.