REDUCTION OF E-CADHERIN LEVELS AND DELETION OF THE ALPHA-CATENIN GENEIN HUMAN PROSTATE-CANCER CELLS

The cadherins are a family of transmembrane glycoproteins responsible for calcium-dependent cell-cell adhesion. This adhesion is mediated by a group of cytoplasmic proteins, the catenins, which act inside the c ell to couple the cadherin molecule to the microfilament cytoskeleton. Dysfunction of E-cadherin-dependent cell-cell adhesion has been demon strated to contribute to the acquisition of invasive potential of mali gnant adenocarcinoma cells. The potential role of alterations of caten in expression in tumor cell invasion is largely unexplored. We have pr eviously found that E-cadherin is frequently down-regulated in clinica l samples of prostate cancer (Umbas, R., Schalken, J. A., Aalders, T. W., Carter, B. S., Karthaus, H. F. M., Schaafsma, H. E., Debruyne, F. M. J., and Isaacs, W. B. Cancer Res., 52: 5104-5109, 1992). In this st udy, we further investigate this adhesion system in both benign and ma lignant human prostate cells in culture. Using antibodies to E-cadheri n and its cytoplasmic accessory protein, alpha-catenin, we find that 5 of 6 human prostate cancer cell lines have reduced or absent levels o f one or the other or both of these molecules when compared to normal prostatic epithelial cells. Only the LNCaP prostate cancer cell line i s indistinguishable from normal prostate epithelium with respect to it s E-cadherin-alpha-catenin complement. Interestingly, the PC-3 line is characterized by the presence of E-cadherin, but the complete lack of alpha-catenin found at both the RNA and protein level. This lack of a lpha-catenin gene expression is explained by Southern analysis, which reveals a homozygous deletion of a large portion of the alpha-catenin gene in PC-3 cells. This loss of alpha-catenin is functionally manifes ted by negligible Ca2+-dependent aggregation of these cells in vitro, when compared to LNCaP cells. These results confirm that E-cadherin-de pendent cell-cell adhesion is frequently aberrant in prostate cancer c ells, and suggest that in a subset of prostate cancers, this adhesion may be inactivated by loss of alpha-catenin rather than E-cadherin its elf Furthermore, these results demonstrate that mutational inactivatio n of the alpha-catenin gene is one mechanism responsible for the loss of normal cell-cell adhesion in prostate cancer.