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The T cell factor/β-Catenin Antagonist PKF115–584 Inhibits Proliferation of Adrenocortical Carcinoma Cells

Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6097 and Université de Nice Sophia Antipolis, 06560 Valbonne, France

Address all correspondence and requests for reprints to: Enzo Lalli, M.D., 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. E-mail: ninino{at}ipmc.cnrs.fr.

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.