CHROMOSOME-5 SUPPRESSES TUMORIGENICITY OF PC3 PROSTATE-CANCER CELLS -CORRELATION WITH REEXPRESSION OF ALPHA-CATENIN AND RESTORATION OF E-CADHERIN FUNCTION

Considerable evidence now exists to support an important role for the E-cadherin-mediated cell-cell adhesion pathway as a suppressor of the invasive phenotype in adenocarcinoma cells. Previous studies have foun d that this pathway is frequently aberrant in prostate cancers, partic ularly those that are Likely to metastasize. In this study, we report on the effects of reestablishment of this pathway in a prostate cancer cell line, PC-3, in which this adhesion system is dysfunctional by vi rtue of a deletion of the gene that codes for alpha-catenin, an E-cadh erin-associated protein necessary for normal E-cadherin function, Re-e xpression of alpha-catenin was accomplished either by transfection of PC-3 cells with a copy of the alpha-catenin cDNA under the control of a heterologous promoter or by microcell-mediated transfer of chromosom e 5, which contains the alpha-catenin gene and its normal regulatory e lements. In both cases, re-expression of alpha-catenin is associated w ith a similar, dramatic alteration in cell morphology, whereby extensi ve cell-cell contact is observed. In the case of transfection of the c DNA, this expression is only transient, because the transfected cells either cease to proliferate or, more commonly, revert to the parental phenotype with concomitant cessation of alpha-catenin expression. In c ontrast, tells containing one or more copies of microcell-transferred chromosome 5 express alpha-catenin in a stable manner and continue to proliferate. Upon injection into nude mice, these latter cells are no longer tumorigenic, or form only slowly growing tumors with greatly ex tended doubling times when compared to the parental PC-3 cells. During passage in culture, clones that contain only one transferred copy of chromosome 5 reproducibly revert to the parental phenotype. This rever sion is associated with loss of the chromosome 5 region containing the alpha-catenin gene and consequent loss of alpha-catenin expression, a s well as re-emergence of tumorigenicity. Transfer of chromosome 5 int o prostate cancer cells that are E-cadherin negative does not result i n either morphological transformation or suppression of tumorigenicity , suggesting that these effects of alpha-catenin expression are depend ent upon concomitant expression of E-cadherin. These data demonstrate the tumor suppressive ability of chromosome 5 in the PC-3 prostate can cer cells and suggest that re-expression of alpha-catenin with resulta nt restoration of E-cadherin function plays a critical role in this pr ocess.