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

Abstract

CONTEXT:

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.

MAIN OUTCOME MEASURES:

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.

• Authors: Mabrouka Doghman, Julie Cazareth, Enzo Lalli
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 93 Issue 8 Pg. 3222-5 (Aug 2008) ISSN: 0021-972X [Print] United States
• PMID: 18544621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TCF Transcription Factors
• beta Catenin

Topics

• Adrenal Cortex Neoplasms (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects)
• Genes, p53
• Humans
• Mutation
• TCF Transcription Factors (antagonists & inhibitors)
• Tumor Cells, Cultured
• beta Catenin (antagonists & inhibitors, genetics)