title: Chromosome 5 suppresses tumorigenicity of PC3 prostate cancer cells: correlation with re-expression of alpha-catenin and restoration of E-cadherin function.
abstract: 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 found that this pathway is frequently aberrant in prostate cancers, particularly those that are likely to metastasize. In this study, we report on the effects of re-establishment of this pathway in a prostate cancer cell line, PC-3, in which this adhesion system is dysfunctional by virtue of a deletion of the gene that codes for alpha-catenin, an E-cadherin-associated protein necessary for normal E-cadherin function. Re-expression 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 chromosome 5, which contains the alpha-catenin gene and its normal regulatory elements. In both cases, re-expression of alpha-catenin is associated with a similar, dramatic alteration in cell morphology, whereby extensive cell-cell contact is observed. In the case of transfection of the cDNA, 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 contrast, cells 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 extended 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 reversion is associated with loss of the chromosome 5 region containing the alpha-catenin gene and consequent loss of alpha-catenin expression, as well as re-emergence of tumorigenicity. Transfer of chromosome 5 into prostate cancer cells that are E-cadherin negative does not result in either morphological transformation or suppression of tumorigenicity, suggesting that these effects of alpha-catenin expression are dependent upon concomitant expression of E-cadherin. These data demonstrate the tumor suppressive ability of chromosome 5 in the PC-3 prostate cancer cells and suggest that re-expression of alpha-catenin with resultant restoration of E-cadherin function plays a critical role in this process.
authors.affiliation: Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Ewing
authors.forename: N
authors.initials: N
authors.lastname: Ru
authors.forename: R A
authors.initials: RA
authors.lastname: Morton
authors.forename: J C
authors.initials: JC
authors.lastname: Robinson
authors.forename: M J
authors.initials: MJ
authors.lastname: Wheelock
authors.forename: K R
authors.initials: KR
authors.lastname: Johnson
authors.forename: J C
authors.initials: JC
authors.lastname: Barrett
authors.forename: W B
authors.initials: WB
authors.lastname: Isaacs
mesh_terms: D000818:Animals; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002895:Chromosomes, Human, Pair 5; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000502:physiology; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051178:alpha Catenin
chemical_list: C495273:CTNNA1 protein, human; D015820:Cadherins; C495272:Ctnna1 protein, mouse; D003598:Cytoskeletal Proteins; D051178:alpha Catenin; D004247:DNA