The FOXM1 Inhibitor RCM‐1 Decreases Carcinogenesis and Nuclear β‐catenin

Abstract

FOXM1, a member of the Forkhead box (FOX) family of transcription factors, has previously been shown to play a critical role in carcinogenesis by inducing cellular proliferation in multiple types of cancer when abnormally upregulated. Our lab previously identified a small molecule compound, Robert Costa Memorial drug‐1 (RCM‐1), through high‐throughput screening as a FOXM1 antagonist in vitro and in an in vivo mouse model of allergen‐mediated lung inflammation. Here, we examined antitumor activities of RCM‐1 using tumor models. Confocal imaging of RCM‐1‐treated tumor cells indicated that reduced cellular proliferation was concordant with inhibition of FOXM1 nuclear localization in these cells. RCM‐1 reduced the incidence and growth of tumor cell colonies in the colony formation assay. Migration assays in vitro demonstrated the ability of RCM‐1 to inhibit migration of tumor cells. In animal models, RCM‐1 treatment inhibited growth of mouse rhabdomyosarcoma Rd76‐9 and human lung adenocarcinoma H2122. RCM‐1 decreased FOXM1 protein levels in treated tumors, reduced tumor cell proliferation and increased tumor cell apoptosis in vivo as detected by immunohistochemical staining. Western blot analysis of cultured tumor cells showed that RCM‐1 decreased protein levels and nuclear localization of β‐catenin, an important constituent of the canonical Wnt signaling pathway, and inhibited protein‐protein interaction between β‐catenin and FOXM1. Altogether, our study provides important evidence of antitumor activity of the small molecule compound RCM‐1, suggesting that RCM‐1 has promising potential as a cancer therapy in the future.Support or Funding InformationPeter K. Lauf Award, Ohio Physiological Society; NIH funding awarded to TK.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.