Antiestrogen enhances N-cadherin-mediated cell-cell adhesion and inhibits cell proliferation in the rat GH3 somatolactotrope cell line
Date of Completion
Biology, Molecular|Biology, Cell
We investigated the effects of the antiestrogen, ICI 182,780, on cell-cell adhesion and cell proliferation in the rat somatolactotrope GH 3 cell line. ICI 182,780 increased adhesion between GH3 cells within 24 hours of treatment as compared to untreated and estrogen-treated controls. This was preceded by an increase in the mRNA and protein levels of the calcium-dependent cell-cell adhesion molecule N-cadherin and its associated protein, β-catenin. All of these effects were overcome by the concurrent addition of estrogen. A purified polyclonal antibody to N-cadherin was able to block the adhesion induced by ICI 182,780, while a non-immune IgG antibody was not, indicating that N-cadherin is at least partially responsible for the increase in cell-cell adhesion. ^ ICI 182,780 also reduced the total number of GH3 cells compared to untreated controls. This was due to a reduction in the rate of proliferation, as the percentage of cells incorporating BrdU was significantly lower in cultures treated with ICI 182,780 as compared to untreated and estrogen-treated controls. As expected, ICI 182,780 also lowered levels of the cell cycle protein cyclin E with respect to untreated controls. Again, all of these effects were overcome by the concurrent addition of estrogen. ^ Increased cadherin-mediated cell-cell adhesion itself inhibited GH 3 cell proliferation in a manner which was partly dependent upon the ability of cadherin to bind β-catenin. Overexpression of E-cadherin stabilized both the α-catenin and β-catenin proteins, and led to a marked increase in cell-cell adhesion, accompanied by a significant decrease in cell proliferation as compared to untransfected and non-expressing transfected controls. Overexpression of an E-cadherin/α-catenin fusion protein lacking the β-catenin binding sites also increased adhesion between GH3 cells, but did not stabilize either α-catenin or β-catenin, and decreased cell proliferation over untransfected and non-expressing transfected controls, but to a lesser extent than E-cadherin expressing cells. This suggests that the mechanism by which E-cadherin suppresses GH3 cell division is partially dependent upon its ability to bind β-catenin. ^ Taken together these results suggest that the reduction in GH3 cell proliferation incurred by ICI 182,780 may be accomplished at least in part by the increase in N-cadherin-mediated cell-cell adhesion, as increased cadherin-mediated cell-cell adhesion itself inhibits GH3 cell proliferation. ^
Heinrich, Cybele Amanda, "Antiestrogen enhances N-cadherin-mediated cell-cell adhesion and inhibits cell proliferation in the rat GH3 somatolactotrope cell line" (1999). Doctoral Dissertations. AAI9959394.