Context: Mutations of the -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: To investigate the effect of the small-molecule inhibitor of the Tcf/-catenin complex PKF115–584 on -catenin – dependent transcription and proliferation of H295R adrenocortical tumor cells, which harbor mutations in CTNNB1 as well as in the TP53 tumor suppressor gene.

Main outcome measures: Immunofluorescence, transient transfection, proliferation assays and flow cytometric analyses were employed.

Results: Nuclear localization of -catenin and constitutive activation of -catenin – dependent transcription was observed in H295R cells. PKF115–584 dose-dependently inhibited -catenin – dependent transcription and H295R proliferation, even in the presence of increased SF-1 levels, which augment proliferation in this cell line. The drug had no effect on HeLa cells, a cell line where the -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/-catenin complex may reveal useful in the treatment of adrenocortical tumors where multiple genetic alterations have accumulated.