The T cell factor/β-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells

Abstract

Context: Mutations of the β-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)/β-catenin complex PKF115-584 on β-catenin-dependent transcription and proliferation of H295R adrenocortical tumor cells, which harbor mutations in CTNNB1 as well as the TP53 tumor suppressor gene. Main Outcome Measures: Immunofluorescence, transient transfection, proliferation assays, and flow cytometric analyses were used. Results: Nuclear localization of β-catenin and constitutive activation of β-catenin-dependent transcription was observed in H295R cells. PKF115-584 dose-dependently inhibited β-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 β-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/β-catenin complex may prove useful in the treatment of adrenocortical tumors in which multiple genetic alterations have accumulated. Copyright © 2008 by The Endocrine Society.