The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells.
BACKGROUND
Mutations of the beta-catenin (CTNNB1) gene are frequently found in adrenocortical tumors. This has important consequences to deregulate the expression of transcriptional targets of the Wnt pathway, which may contribute to tumorigenesis.


OBJECTIVE
The objective of the study was to investigate the effect of the small-molecule inhibitor of the T cell factor (Tcf)/beta-catenin complex PKF115-584 on beta-catenin-dependent transcription and proliferation of H295R adrenocortical tumor cells, which harbor mutations in CTNNB1 as well as the TP53 tumor suppressor gene.


METHODS
Immunofluorescence, transient transfection, proliferation assays, and flow cytometric analyses were used.


RESULTS
Nuclear localization of beta-catenin and constitutive activation of beta-catenin-dependent transcription was observed in H295R cells. PKF115-584 dose-dependently inhibited beta-catenin-dependent transcription and H295R proliferation, even in the presence of increased steroidogenic factor-1 levels, which augment proliferation in this cell line. The drug had no effect on HeLa cells, a cell line in which the beta-catenin pathway is not activated. PKF115-584 decreased the percentage of H295R cells in S-phase and increased the percentage of apoptotic cells.


CONCLUSIONS
Inhibitors of the Tcf/beta-catenin complex may prove useful in the treatment of adrenocortical tumors in which multiple genetic alterations have accumulated.
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6097, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
Mabrouka
M
Doghman
Julie
J
Cazareth
Enzo
E
Lalli
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics
D051820:TCF Transcription Factors; D051176:beta Catenin