Reference - Detail
|Author||Arioka M, Takahashi-Yanaga F, Kubo M, Igawa K, Tomooka K, Sasaguri T.|
|Title||Anti-tumor effects of differentiation-inducing factor-1 in malignant melanoma: GSK-3-mediated inhibition of cell proliferation and GSK-3-independent suppression of cell migration and invasion.|
Differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum strongly inhibits the proliferation of various mammalian cells through the activation of glycogen synthase kinase-3 (GSK-3). To evaluate DIF-1 as a novel anti-cancer agent for malignant melanoma, we examined whether DIF-1 has anti-proliferative, anti-migratory, and anti-invasive effects on melanoma cells using in vitro and in vivo systems. DIF-1 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via GSK-3 in mouse (B16BL6) and human (A2058) malignant melanoma cells, and thereby strongly inhibited their proliferation. DIF-1 suppressed the canonical Wnt signaling pathway by lowering the expression levels of transcription factor 7-like 2 and β-catenin, key transcription factors in this pathway. DIF-1 also inhibited cell migration and invasion, reducing the expression of matrix metalloproteinase-2; however, this effect was not dependent on GSK-3 activity. In a mouse lung tumor formation model, repeated oral administrations of DIF-1 markedly reduced melanoma colony formation in the lung. These results suggest that DIF-1 inhibits cell proliferation by a GSK-3-dependent mechanism and suppresses cell migration and invasion by a GSK-3-independent mechanism. Therefore, DIF-1 may have a potential as a novel anti-cancer agent for the treatment of malignant melanoma.
|MeSH||Animals Antineoplastic Agents / adverse effects Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Enzyme Activation / drug effects Female Glycogen Synthase Kinase 3 / antagonists & inhibitors Glycogen Synthase Kinase 3 / chemistry Glycogen Synthase Kinase 3 / genetics Glycogen Synthase Kinase 3 / metabolism* Hexanones / adverse effects Hexanones / pharmacology Hexanones / therapeutic use* Humans Hydrocarbons, Chlorinated / adverse effects Hydrocarbons, Chlorinated / pharmacology Hydrocarbons, Chlorinated / therapeutic use* Lung / drug effects Lung / metabolism Lung / pathology Lung Neoplasms / drug therapy Lung Neoplasms / metabolism Lung Neoplasms / pathology Melanoma / drug therapy* Melanoma / metabolism Melanoma / pathology Melanoma, Experimental / drug therapy Melanoma, Experimental / metabolism Melanoma, Experimental / pathology Mice Mice, Inbred C57BL Neoplasm Invasiveness / pathology Neoplasm Invasiveness / prevention & control Neoplasm Proteins / agonists Neoplasm Proteins / antagonists & inhibitors Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* RNA Interference Random Allocation Tumor Burden / drug effects Wnt Signaling Pathway / drug effects*|
|Human and Animal Cells||B16/BL6(RCB2638)|