Beta-catenin-related anomalies in apoptosis-resistant and hormone-refractory prostate cancer cells.
OBJECTIVE
beta-Catenin is a critical end component of the wnt signaling pathway that regulates cell growth, apoptosis, and migratory behavior in response to intercellular adhesion molecules. The aim of this study was to evaluate abnormalities of beta-catenin protein expression, subcellular localization, and activity in an in vitro model of acquired apoptosis-resistance in cultured PC cells and in primary human prostate cancers (PrCa).


METHODS
Apoptosis-resistant human prostate cancer cell line variants were derived from parental LNCaP cells by repeated brief exposure to apoptotic stimuli. The derivative and parental cells were analyzed for beta-catenin expression and intracellular localization using cell fractionation and Western blotting procedures. Endogenous transcriptional activity from the TCF/LEF-1 response element was also studied in these variants after transfection with a beta-catenin sensitive reporter plasmid. Finally, beta-catenin protein expression and intracellular localization were evaluated on 212 patients [122 localized PrCa and 90 hormone-refractory (HRPC) PrCa specimens by immunohistochemistry].


RESULTS
Western blot analysis showed that the intracellular partitioning of beta-catenin was shifted from the membrane fraction in parental cells to the cytoplasmic/nuclear fractions of the apoptosis-resistant cell lines. Coordinately, transcriptional activity from a TCF/LEF-promoted reporter plasmid was increased significantly in the apoptosis-resistant lines. In the primary prostate tumors analyzed, cytoplasmic and/or nuclear beta-catenin expression was correlated statistically with the HRPC status and Gleason score. In the group of localized PrCa, abnormal beta-catenin expression tended to be associated with a higher Gleason score and with pT3 disease. No mutation was found in patients with HRPC and abnormal beta-catenin expression.


CONCLUSIONS
These data suggest that anomalies of beta-catenin expression occur in PrCa and that these anomalies are associated with disease progression, especially to the therapeutic-resistant state.
Department of Urology, Assistance Publique des Hôpitaux de Paris-CHU Mondor, 94000 Créteil, France. adelataille@hotmail.com
Alexandre
A
de la Taille
Mark A
MA
Rubin
Min-Wei
MW
Chen
Francis
F
Vacherot
Sixtina Gil-Diez
SG
de Medina
Martin
M
Burchardt
Ralph
R
Buttyan
Dominique
D
Chopin
D000328:Adult; D000368:Aged; D017209:Apoptosis; D002462:Cell Membrane; D002467:Cell Nucleus; D003593:Cytoplasm; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D013347:Subcellular Fractions; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin