Anti-angiogenic effects of differentiation-inducing factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/β-catenin signaling pathway.

Tatsuya Yoshihara, Fumi Takahashi, Fumie Shiraishi, Sachio Morimoto, Yutaka Watanabe, Masato Hirata, Sumio Hoka, Toshiyuki Sasaguri

Research output: Contribution to journalArticle

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Abstract

Differentiation-inducing factor-1 (DIF-1) is a putative morphogen that induces cell differentiation in Dictyostelium discoideum. DIF-1 inhibits proliferation of various mammalian tumor cells by suppressing the canonical Wnt/β-catenin signaling pathway. To assess the potential of a novel cancer chemotherapy based on the pharmacological effect of DIF-1, we investigated whether DIF-1 exhibits anti-angiogenic effects in vitro and in vivo. DIF-1 not only inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) by restricting cell cycle in the G0/G1 phase and degrading cyclin D1, but also inhibited the ability of HUVECs to form capillaries and migrate. Moreover, DIF-1 suppressed VEGF- and cancer cell-induced neovascularization in Matrigel plugs injected subcutaneously to murine flank. Subsequently, we attempted to identify the mechanism behind the anti-angiogenic effects of DIF-1. We showed that DIF-1 strongly decreased vascular endothelial growth factor receptor-2 (VEGFR-2) expression in HUVECs by inhibiting the promoter activity of human VEGFR-2 gene, though it was not caused by inhibition of the Wnt/β-catenin signaling pathway. These results suggested that DIF-1 inhibits angiogenesis both in vitro and in vivo, and reduction of VEGFR-2 expression is involved in the mechanism. A novel anti-cancer drug that inhibits neovascularization and tumor growth may be developed by successful elucidation of the target molecules for DIF-1 in the future.

Original languageEnglish
Number of pages1
JournalMolecular cancer
Volume9
DOIs
Publication statusPublished - Jan 1 2010

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Catenins
Vascular Endothelial Growth Factor Receptor-2
Wnt Signaling Pathway
Human Umbilical Vein Endothelial Cells
Neoplasms
1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone
Cell Cycle Resting Phase
Dictyostelium
Cyclin D1
G1 Phase
Vascular Endothelial Growth Factor A
Cell Differentiation
Cell Cycle
Pharmacology
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research

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Anti-angiogenic effects of differentiation-inducing factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/β-catenin signaling pathway. / Yoshihara, Tatsuya; Takahashi, Fumi; Shiraishi, Fumie; Morimoto, Sachio; Watanabe, Yutaka; Hirata, Masato; Hoka, Sumio; Sasaguri, Toshiyuki.

In: Molecular cancer, Vol. 9, 01.01.2010.

Research output: Contribution to journalArticle

Yoshihara, Tatsuya ; Takahashi, Fumi ; Shiraishi, Fumie ; Morimoto, Sachio ; Watanabe, Yutaka ; Hirata, Masato ; Hoka, Sumio ; Sasaguri, Toshiyuki. / Anti-angiogenic effects of differentiation-inducing factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/β-catenin signaling pathway. In: Molecular cancer. 2010 ; Vol. 9.
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