The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear β-Catenin.

Abstract

The oncogenic transcription factor FOXM1 has been previously shown to play a critical role in carcinogenesis by inducing cellular proliferation in multiple cancer types. A small-molecule compound, Robert Costa Memorial drug-1 (RCM-1), has been recently identified from high-throughput screen as an inhibitor of FOXM1 in vitro and in mouse model of allergen-mediated lung inflammation. In the present study, we examined antitumor activities of RCM-1 using tumor models. Treatment with RCM-1 inhibited tumor cell proliferation as evidenced by increased cell-cycle duration. Confocal imaging of RCM-1-treated tumor cells indicated that delay in cellular proliferation was concordant with inhibition of FOXM1 nuclear localization in these cells. RCM-1 reduced the formation and growth of tumor cell colonies in the colony formation assay. In animal models, RCM-1 treatment inhibited growth of mouse rhabdomyosarcoma Rd76-9, melanoma B16-F10, and human H2122 lung adenocarcinoma. RCM-1 decreased FOXM1 protein in the tumors, reduced tumor cell proliferation, and increased tumor cell apoptosis. RCM-1 decreased protein levels and nuclear localization of β-catenin, and inhibited protein-protein interaction between β-catenin and FOXM1 in cultured tumor cells and in vivo Altogether, our study provides important evidence of antitumor potential of the small-molecule compound RCM-1, suggesting that RCM-1 can be a promising candidate for anticancer therapy.

• Authors: Samriddhi Shukla, David Milewski, Arun Pradhan, Nihar Rama, Kathryn Rice, Tien Le, Matthew J Flick, Sara Vaz, Xueheng Zhao, Kenneth D Setchell, Elsa Logarinho, Vladimir V Kalinichenko, Tanya V Kalin
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 7 Pg. 1217-1229 (07 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31040162 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• CTNNB1 protein, human
• Forkhead Box Protein M1
• beta Catenin

Topics

• Animals
• Cell Line, Tumor
• Disease Models, Animal
• Forkhead Box Protein M1 (genetics)
• Humans
• Mice
• Transfection
• beta Catenin (genetics, metabolism)