Regulation of E-cadherin and beta-catenin by Ca2+ in colon carcinoma is dependent on calcium-sensing receptor expression and function

Int J Cancer. 2007 Oct 1;121(7):1455-62. doi: 10.1002/ijc.22858.


An siRNA directed against the extracellular calcium-sensing receptor (CaSR) was used to down-regulate this protein in CBS colon carcinoma cells. In additional studies, we utilized a variant of the parental CBS line that demonstrates CaSR expression but does not upregulate this protein in response to extracellular Ca(2+). In neither the siRNA-transfected cells nor the Ca(2+)-nonresponsive variant cells did inclusion of Ca(2+) in the culture medium inhibit proliferation or induce morphological alterations. Extracellular Ca(2+) also failed to induce E-cadherin production or a shift in beta-catenin from the cytoplasm to the cell membrane. In mock-transfected cells and in a Ca(2+)-responsive variant line derived from the same parental CBS cells, Ca(2+) treatment resulted in growth-reduction. This was accompanied by increased E-cadherin production and a shift in beta-catenin distribution from the cytoplasm to the cell membrane. Additionally, down-regulation of c-myc and cyclin D1 expression was observed in mock-transfected cells and in the Ca(2+)-responsive variant line (along with reduced T cell factor transcriptional activation). Neither c-myc nor cyclin D1 was significantly down-regulated in the siRNA-transfected cells or in the Ca(2+)-nonresponsive variant cells upon Ca(2+) stimulation. In histological sections of human colon carcinoma CaSR was significantly reduced as compared to the level in normal colonic crypt epithelial cells. Where CaSR expression was high, strong surface staining for E-cadherin and beta-catenin was observed. Where CaSR expression was reduced, beta-catenin surface expression was likewise reduced.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cadherins / metabolism*
  • Calcium / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Humans
  • Immunohistochemistry
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • RNA, Small Interfering / genetics
  • Receptors, Calcium-Sensing / genetics
  • Receptors, Calcium-Sensing / metabolism
  • Receptors, Calcium-Sensing / physiology*
  • Transfection
  • beta Catenin / metabolism*


  • Cadherins
  • RNA, Small Interfering
  • Receptors, Calcium-Sensing
  • beta Catenin
  • Calcium