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

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• 作者：Tamaki Hirano ; Reiko Satow ; Asami Kato ; Mana Tamura ; Yumi Murayama ; Hideyuki Saya ; Hirotatsu Kojima ; Tetsuo Nagano ; Takayoshi Okabe ; Kiyoko Fukami
• 关键词：MTX ; methotrexate ; EMT ; epithelial&ndash ; mesenchymal transition ; FBS ; fetal bovine serum
• 刊名：Biochemical Pharmacology
• 出版年：15 November, 2013
• 年：2013
• 卷：86
• 期：10
• 页码：1419-1429
• 全文大小：2000 K

文摘

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.