Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway

Yusuke Komi, Yukihisa Sogabe, Naoto Ishibashi, Yasufumi Sato, Hisataka Moriwaki, Kentaro Shimokado, Soichi Kojima

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Acyclic retinoid (ACR) is currently under clinical trial as an agent to suppress the recurrence of hepatocellular carcinoma (HCC) through its ability to induce apoptosis in premature HCC cells. ACR has an anticancer effect in vivo as well, although it shows weak apoptosis-inducing activity against mature HCC cells, suggesting the existence of an additional action mechanism. In this study, we investigated the antiangiogenic activity of ACR. ACR inhibited angiogenesis within chicken chorioallantoic membrane (CAM) in as similar a manner as all-trans retinoic acid (atRA). Although suppression of angiogenesis by atRA was partially rescued by the simultaneous addition of angiopoietin-1, suppression of angiogenesis by ACR was not rescued under the same condition at all. Conversely, although suppression of angiogenesis by ACR was partially inverted by the simultaneous addition of vascular endothelial growth factor (VEGF), suppression of angiogenesis by atRA was not affected under the same condition. These results suggested that mechanisms underlying the suppression of angiogenesis by ACR and atRA were different. ACR selectively inhibited the phosphorylation of VEGF receptor 2 (VEGFR2) and of extracellular signal-regulated kinase (ERK) without changing their protein expression levels, and inhibited endothelial cell growth, migration, and tube formation. The inhibition of the phosphorylation of ERK, endothelial growth, migration, tube formation, and angiogenesis by ACR was rescued by the overexpression of constitutively active mitogen-activated protein kinase (MAPK). Finally, ACR, but not atRA, inhibited HCC-induced angiogenesis in a xenografted CAM model. These results delineate the novel activity of ACR as an antiangiogenic through a strong inhibition of the VEGFR2 MAPK pathway.

Original languageEnglish
Pages (from-to)52-60
Number of pages9
JournalLaboratory Investigation
Volume90
Issue number1
DOIs
Publication statusPublished - 2010 Jan

Keywords

  • ACR
  • HCC
  • MAPK pathway
  • Phosphorylation
  • Tumor angiogenesis
  • VEGF receptor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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