title: Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness.
abstract: Tumor dissemination and invasive behavior are associated with a majority of cancer-related mortality cases. Loss of E-cadherin, which is caused by several tumor-promoting factors, is associated with metastasis and poor prognosis in many neoplasms. In this study, we aimed to identify small molecule compounds that restore the expression of E-cadherin, because these molecules are most likely to suppress tumor malignancy by restoring E-cadherin function and/or by inhibiting signals that suppress E-cadherin expression. Here, we developed a fluorescence screen system based on E-cadherin expression. A pilot drug library screen revealed that methotrexate (MTX) strongly induces E-cadherin expression in a colorectal cancer cell line, SW620. From the screen for 9600 compounds, we identified 9 hit compounds, which restored the expression of E-cadherin in SW620 and/or a melanoma cell line, SK-MEL-28. We confirmed that MTX and the other identified compounds transcriptionally promote E-cadherin expression. Among these, 2 compounds suppressed migration/invasion capacity in colorectal cancer cells and 3 in melanoma cells. A compound reduced SW620 migration and invasion with subtle effects on cell viability in SW620, SK-MEL-28, and a non-tumor cell line, HaCaT, with decrease in AKT and ERK1/2 protein levels. One of the other compounds reduced SK-MEL-28 cell migration and invasion and affected the viability only of SW620 and SK-MEL-28 cells but not HaCaT cells. These results suggest that these compounds would be attractive lead molecules as anti-metastasis agents.
authors.affiliation: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo 192-0392, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Hirano
authors.forename: Reiko
authors.initials: R
authors.lastname: Satow
authors.forename: Asami
authors.initials: A
authors.lastname: Kato
authors.forename: Mana
authors.initials: M
authors.lastname: Tamura
authors.forename: Yumi
authors.initials: Y
authors.lastname: Murayama
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
mesh_terms: D000230:Adenocarcinoma; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D015820:Cadherins / Q000096:biosynthesis*; D002460:Cell Line; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D008545:Melanoma; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D054852:Small Molecule Libraries; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D008727:Methotrexate
keywords: Colorectal cancer; Compound; E-cadherin; EMT; FBS; MTX; Melanoma; Methotrexate; Small molecule screen; epithelial–mesenchymal transition; fetal bovine serum; methotrexate