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


RESULTS
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.


CONCLUSIONS
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.
Yoshihara
Tatsuya
T
Department of Clinical Pharmacology, Kyushu University, Fukuoka, Japan.
Takahashi-Yanaga
Fumi
F
Shiraishi
Fumie
F
Morimoto
Sachio
S
Watanabe
Yutaka
Y
Hirata
Masato
M
Hoka
Sumio
S
Sasaguri
Toshiyuki
T
D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D007150:Immunohistochemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C490570:Differentiation-inducing factor-1, Dictyostelium; D006588:Hexanones; D006843:Hydrocarbons, Chlorinated; D051153:Wnt Proteins; D051176:beta Catenin; D040301:Vascular Endothelial Growth Factor Receptor-2