Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness

Tamaki Hirano, Reiko Satow, Asami Kato, Mana Tamura, Yumi Murayama, Hideyuki Saya, Hirotatsu Kojima, Tetsuo Nagano, Takayoshi Okabe, Kiyoko Fukami

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1419-1429
Number of pages11
JournalBiochemical Pharmacology
Volume86
Issue number10
DOIs
Publication statusPublished - 2013 Oct 4

Keywords

  • Colorectal cancer
  • Compound
  • E-cadherin
  • Melanoma
  • Methotrexate
  • Small molecule screen

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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  • Cite this

    Hirano, T., Satow, R., Kato, A., Tamura, M., Murayama, Y., Saya, H., Kojima, H., Nagano, T., Okabe, T., & Fukami, K. (2013). Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness. Biochemical Pharmacology, 86(10), 1419-1429. https://doi.org/10.1016/j.bcp.2013.09.001