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

masaki arioka, Fumi Takahashi-Yanaga, Momoko Kubo, Kazunobu Igawa, Katsuhiko Tomooka, Toshiyuki Sasaguri

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Abstract

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.

Original languageEnglish
Pages (from-to)31-48
Number of pages18
JournalBiochemical Pharmacology
Volume138
DOIs
Publication statusPublished - Aug 15 2017

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Glycogen Synthase Kinase 3
Cell proliferation
Cell Movement
Tumors
Melanoma
Cell Proliferation
Neoplasms
Wnt Signaling Pathway
T Cell Transcription Factor 1
1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone
Catenins
Lung
Dictyostelium
Matrix Metalloproteinase 2
Cyclin D1
Oral Administration
Transcription Factors
Chemical activation
Cells
Degradation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

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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",
abstract = "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.",
author = "masaki arioka and Fumi Takahashi-Yanaga and Momoko Kubo and Kazunobu Igawa and Katsuhiko Tomooka and Toshiyuki Sasaguri",
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T2 - GSK-3-mediated inhibition of cell proliferation and GSK-3-independent suppression of cell migration and invasion

AU - arioka, masaki

AU - Takahashi-Yanaga, Fumi

AU - Kubo, Momoko

AU - Igawa, Kazunobu

AU - Tomooka, Katsuhiko

AU - Sasaguri, Toshiyuki

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