title: Induction of calcium sensing receptor in human colon cancer cells by calcium, vitamin D and aquamin: Promotion of a more differentiated, less malignant and indolent phenotype.
abstract: The calcium sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells and functions as a tumor suppressor. Cancer cells that do not express CaSR (termed CaSR null) are highly malignant while acquisition of CaSR expression in these cells circumvents the malignant phenotype. We hypothesize that chemopreventive agents mediate their action through the induction of CaSR. Here, we compare the effectiveness of Ca(2+), vitamin D, and Aquamin (a marine algae product containing Ca(2+), magnesium and detectable levels of 72 additional minerals) on the induction of CaSR in the CBS and HCT116 human colon carcinoma cell lines and the corresponding CaSR null cells isolated from these lines. All three agonists induced CaSR mRNA and protein expression and inhibited cellular proliferation in the parental and CaSR null cells. Aquamin was found to be most potent in this regard. Induction of CaSR expression by these agonists resulted in demethylation of the CaSR gene promoter with a concurrent increase in CaSR promoter reporter activity. However, demethylation per se did not induce CaSR transcription. Induction of CaSR expression resulted in a down-regulated expression of tumor inducers and up-regulated expression of tumor suppressors. Again, Aquamin was found to be most potent in these biologic effects. This study provides a rationale for the use of a multi-mineral approach in the chemoprevention of colon cancer and suggests that induction of CaSR may be a measure of the effectiveness of chemopreventive agents.
authors.affiliation: Department of Microbiology, Immunology and Cell Biology Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IIllinois.
authors.forename: Navneet
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Muhammad N
authors.initials: MN
authors.lastname: Aslam
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.affiliation: Department of Microbiology, Immunology and Cell Biology Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IIllinois.
authors.forename: Subhas
authors.initials: S
authors.lastname: Chakrabarty
mesh_terms: D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002118:Calcium / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018899:CpG Islands / Q000187:drug effects; D019587:Dietary Supplements; D045325:HCT116 Cells; D006801:Humans; D008903:Minerals / Q000627:therapeutic use*; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000627:therapeutic use*
chemical_list: D016588:Anticarcinogenic Agents; C572820:Aquamin; D008903:Minerals; D044169:Receptors, Calcium-Sensing; D014807:Vitamin D; D002118:Calcium
keywords: CaSR; aquamin; calcium; chemoprevention; vitamin D