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

Abstract

Abstract.We have previously reported that by inducing calcium sensing receptor (CaSR), calcitriol, the active form of vitamin D, promoted the sensitivity of the human colon carcinoma cells to anticancer drugs. In the current study we tested several other potential CaSR modulators, calcipotriol and the effective components of Chinese herbal medicine lentinan, for their functions in inducing CaSR expression in human colon carcinoma cell line CBS, Moser, Fet, and SW480 cells and subsequently promoting sensitivity of the cells to anticancer drugs. Calcipotriol and lentinan suppressed invasion of the colon carcinoma cells and enhanced the cytotoxicity of anticancer regimen FOLFIRI to cells in culture or in anchorage-independent growth. In the mechanism study we found that calcipotriol and lentinan suppressed protein expression and gene transcriptional activities of survivin and thymidylate synthase, increased E-cadherin cell membrane localization and complex formation of E-cadherin and ß-catenin, and repressed TCF4 transcriptional activation. These effects were attenuated, however, in CaSR knocked-down cells, indicating that CaSR was required in the pathway. We concluded that calcipotriol and lentinan are efficient in promoting chemosensitivity in colon carcinoma cells. Since both compounds have much less side effects than calcitriol in clinic, they have greater potential to be applied as supplements of colon cancer therapy. IntroductionCaSR is a G protein-coupled receptor originally identified in human parathyroid gland where it senses the instant changes in extracellular Ca 2+ levels (1). It was discovered later that CaSR is also expressed in a wide variety of human tissues, including human colon cancer and other cancer cells (2-4). The potential function of CaSR in colon epithelium is involved in promoting the progress of cell differentiation. In normal colon epithelium, there is no CaSR expression at the bottom of the colonic crypts where undifferentiated stem cells are located and responsible for epithelial tissue renewal (5,6). As the epithelial cells differentiate and migrate upward to the top of the crypt, the cells acquire a gradient increase in the expression of the CaSR (5,6). 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). Through this mechanism, VD induces P1 and P2 pro...

The Invasion and Metastasis Promotion Role of CD97 Small Isoform in Gastric Carcinoma

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Comparative Expression Study of the Endo–G Protein Coupled Receptor (GPCR) Repertoire in Human Glioblastoma Cancer Stem-like Cells, U87-MG Cells and Non Malignant Cells of Neural Origin Unveils New Potential Therapeutic Targets

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“…In gastric tumor tissues, the expression of CD55 was well correlated with that of CD97. Particularly, strong staining of CD97 and CD55 was observed in the cytoplasm of the signet ring cell carcinoma of patients, which suggests that CD97 may be involved in the remodelling of adhesive contacts of the invading tumor cells by direct receptor-ligand interactions [18]. In colorectal carcinomas, CD97 and CD55 are overexpressed in the tumor environment.…”