Dietary calcium and growth modulation of human colon cancer cells: role of the extracellular calcium-sensing receptor.
Using the human colon adenocarcinoma-derived cell line Caco-2, we investigated the possible role of the Ca2+-sensing receptor (CaR) in mediating effects of extracellular Ca2+ on cellular proliferation. Caco-2 cells respond to low ambient [Ca2+]o by activation of the protein kinase C-signaling pathway, leading to upregulation of c-myc mRNA expression and thereby, finally, to alleviation from the G1/S phase control of the cell cycle. This proliferative response can be reverted by activation of the CaR either through raising [Ca2+]o or, respectively, by using the CaR agonist Gd3+ as a substitute for Ca2+. The inhibitory effect of [Ca2+]o on cell replication exhibits saturation kinetics (IC50 = 0.045 mM), indicating the existence of a highly sensitive CaR operating at low ambient [Ca2+]o. Specific immunostaining revealed the presence of CaR-positive cells in the crypt epithelium of normal human colonic mucosa as well as in glandular (i.e., differentiated structures) of carcinomatous lesions. This could provide a rationale for use of calcium supplements for intervention in early phases of colon tumorigenesis.
Kállay
E
E
Department of General and Experimental Pathology, University Vienna Medical School, Austria.
Bajna
E
E
Wrba
F
F
Kriwanek
S
S
Peterlik
M
M
Cross
H S
HS
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002136:Calcium, Dietary / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction
D002136:Calcium, Dietary; D002135:Calcium-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011493:Protein Kinase C; D000469:Alkaline Phosphatase