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The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear ?-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 ?-catenin, and inhibited protein-protein interaction between ?-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.

SUBMITTER: Shukla S

PROVIDER: S-EPMC7341442 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Shukla Samriddhi S Milewski David D Pradhan Arun A Rama Nihar N Rice Kathryn K Le Tien T Flick Matthew J MJ Vaz Sara S Zhao Xueheng X Setchell Kenneth D KD Logarinho Elsa E Kalinichenko Vladimir V VV Kalin Tanya V TV

Molecular cancer therapeutics 20190430 7

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 <i>in vitro</i> 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 inh ...[more]

PMID: 31040162

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Project description:BackgroundMost of the endometrial cancer (EC) patients are diagnosis in early stage with a good prognosis while the patients with locally advanced recurrent or metastatic result in a poor prognosis. Adjuvant therapy could benefit the prognosis of patients with high-risk factors. Unfortunately, the molecular classification of great prognostic value has not yet reached an agreement and need to be further refined. The present study aims to identify new targets that have prognostic value in EC based on the method of EC patient-derived organ-like organs (PDOs), and further investigate their efficacy and mechanism.MethodsThe Cancer Genome Atlas (TCGA) database was used to determine SNORD14E expression. The effects of SNORD14E were investigated using CCK8, Transwell, wound-healing assays, and a xenograft model experiment; apoptosis was measured by flow cytometry. Antisense oligonucleotide (ASO) targeting SNORD14E was designed and patient-derived organoids (PDO) models in EC patients was established. A xenograft mouse and PDO model were employed to evaluate the effects of ASO targeting SNORD14E. RNA-seq, Nm-seq, and RNA immunoprecipitation (RIP) experiments were employed to confirm the alternative splicing (AS) and modification induced by SNORD14E. A minigene reporter gene assay was conducted to confirm AS and splicing factors on a variable exon. Actinomycin-d (Act-D) and Reverse Transcription at Low deoxy-ribonucleoside triphosphate concentrations followed by PCR (RTL-P) were utilized to confirm the effects of 2'-O methylation modification on FOXM1.ResultsWe found that SNORD14E was overexpressed in EC tissues and patients with high expressed SNORD14E were distributed in the TCGA biomolecular classification subgroups without difference. Further, SNORD14E could reduce disease-free survival (DFS) and recurrence free survival (RFS) of EC patients. SNORD14E promoted proliferation, migration, and invasion and inhibited the apoptosis of EC cells in vitro. ASOs targeting SNORD14E inhibited cell proliferation, migration, invasion while promoted cell apoptosis. ASOs targeting SNORD14E inhibited tumor growth in the xenograft mouse model. TCGA-UCEC database showed that the proportion of patients with high expression of SNORD14E in middle-high risk and high-risk patients recommended by EMSO-ESGO-ESTRO guidelines for adjuvant therapy is more than 50%. Next, we enrolled 8 cases of high-risk and high-risk EC patients according to EMSO-ESGO-ESTRO guidelines and successfully constructed EC-PDOs. ASOs targeting SNORD14E inhibited the EC-PDO growth. Mechanistically, SNORD14E could recognize the mRNA of FOXM1 and recruit SRSF1 to promote the shearing of the variable exon VIIa of FOXM1, resulting in the overexpression of the FOXM1 malignant subtypes FOXM1b and FOXM1c. In addition, SNORD14E modified FOXM1 mRNA with 2`-O-methylation, which prolonged the half-life of FOXM1 mRNA. The nucleus accumulation of β-catenin caused by aberrant FOXM1 expression led to EC progression.ConclusionsASO targeting SNORD14E can be an effective treatment for EC.

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

Publications

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

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