Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma.

Abstract

The forkhead box transcription factor FOXM1 is considered to be a promising target for cancer therapy. However, the significance of FOXM1 in tumors harboring mutation in p53, which is very common, is unclear. In this study, we investigated the efficacy of FoxM1 targeting in spontaneous p53-null tumors using genetic ablation as well as using a peptide inhibitor of FOXM1. We show that conditional deletion of FoxM1 inhibits growth of the p53-null thymic lymphoma and sarcoma cells. In addition, deletion of FoxM1 induces apoptotic cell death of the p53-null tumors, accompanied by reduced expression of the FOXM1 target genes survivin and Bmi1. An ARF-derived peptide that inhibits the activity of FOXM1, by targeting it to the nucleolus, also induces apoptosis in the p53-null sarcoma and lymphoma, leading to a strong inhibition of their metastatic colonization. Together, our observations suggest that FOXM1 is critical for survival and growth of the p53-null lymphoma and sarcoma and provide proof-of-principle that FOXM1 is an effective therapeutic target for sarcoma and lymphoma carrying loss of function mutation in p53.

• Authors: Zebin Wang, Yu Zheng, Hyun Jung Park, Jing Li, Janai R Carr, Yi-ju Chen, Megan M Kiefer, Dragana Kopanja, Srilata Bagchi, Angela L Tyner, Pradip Raychaudhuri
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 5 Pg. 759-67 (May 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23427295 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2013 AACR

Chemical References

• Birc5 protein, mouse
• Bmi1 protein, mouse
• Cdkn2a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p16
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• Foxm1 protein, mouse
• Inhibitor of Apoptosis Proteins
• Peptides
• Proto-Oncogene Proteins
• Repressor Proteins
• Survivin
• Tumor Suppressor Protein p53
• Polycomb Repressive Complex 1

Topics

• Allografts
• Animals
• Apoptosis (drug effects, genetics)
• Cell Survival (drug effects, genetics)
• Cyclin-Dependent Kinase Inhibitor p16 (chemistry)
• Disease Models, Animal
• Forkhead Box Protein M1
• Forkhead Transcription Factors (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Lymphoma (genetics, metabolism)
• Mice
• Mice, Knockout
• Peptides (pharmacology)
• Polycomb Repressive Complex 1 (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Sarcoma (genetics, metabolism)
• Survivin
• Thymus Neoplasms (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics)