Role of Notch-1 and E-Cadherin in the Differential Response to Calcium in Culturing Normal versus Malignant Prostate Cells

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Abstract
A panel of expression markers was validated and used to document that, when radical prostatectomy specimens are cultured in low (i.e., 400 μmol/L, Notch-1 conformationally is no longer constitutively active but requires cell-cell contact for reciprocal binding of Jagged-1 ligands and Notch-1 receptors between adjacent transit-amplifying cells to activate their survival signaling. Such cell-cell contact is enhanced by the elevated Ca2+ inducing an E-cadherin conformation allowing homotypic interaction between transit-amplifying cells. Such Ca2+-dependent, E-cadherin-mediated interaction, however, results in cell aggregation, stratification, and inhibition of proliferation of transit-amplifying cells via contact inhibition–induced up-regulation of p27/kip1 protein. In addition, transit-amplifying cells not contacting other cells undergo squamous differentiation into cornified (i.e., 1% SDS insoluble) envelopes and death in the elevated Ca2+ medium. Stratification and contact inhibition induced by elevated Ca2+ are dependent on E-cadherin–mediated homotypic interaction between transit-amplifying cells as shown by their prevention in the presence of a cell-impermanent, E-cadherin neutralizing antibody. In contrast to growth inhibition of normal transit-amplifying cells, supplementation of low-Ca2+-SFD medium with 10% FCS and raising the Ca2+ to >600 μmol/L stimulates the growth of all prostate cancer cell lines tested. Additional results document that, at physiologic levels of Ca2+ (i.e., >600 μmol/L), prostatic cancer cells are not contact inhibited by E-cadherin interactions and Notch-1 signaling is no longer required for survival but instead becomes one of multiple signaling pathways for proliferation of prostatic cancer cells. These characteristic changes are consistent with prostate cancer cells' ability to metastasize to bone, a site of high-Ca2+ levels.