4-O-methylascochlorin stabilizes hypoxia-inducible factor-1 in a manner different from hydroxylase inhibition by iron chelating or substrate competition

Junji Magae, Chiharu Furukawa, Shigefumi Kuwahara, Yun Jeong Jeong, Hiroo Nakajima, Young Chae Chang

Research output: Contribution to journalArticle

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays essential roles in human diseases including cancer. The synthetic ascochlorin derivative 4-O-methylascochlorin stabilizes HIF-1α protein, and activates its transcriptional activity, resulting to induce gene expression of its downstream targets such as VEGF and GLUT-1. Here, we quantified protein level of HIF-1α in human osteosarcoma U2OS cells treated with ascochlorin-related compounds and typical HIF-1α stabilizers to characterize properties of HIF-1α stabilization by 4-O-methylascochlorin. Structure–activity relationship studies suggested that the aromatic moiety and hydrophobic substitution of the 4′-hydroxyl group are important for HIF-1α stabilization by ascochlorin-related compounds. 4-O-Methylascochlorin-induced HIF-1α stabilization was suppressed by ascorbic acid and compound C, but not by Fe(II), whereas ascorbic acid only suppressed HIF-1α stabilization by dimethyloxaloylglycine, an analog of the HIF-1 hydroxylase substrate. Fe(II) completely suppressed iron chelator-induced stabilization. These results suggest that ascochlorin-related compounds stabilize HIF-1α in a manner distinct from iron chelating or substrate competition.

Original languageEnglish
Pages (from-to)2244-2248
Number of pages5
JournalBioscience, Biotechnology and Biochemistry
Volume83
Issue number12
DOIs
Publication statusPublished - 2019 Jan 1

Keywords

  • 4-O-methylascochlorin
  • Ascochlorin
  • Ascofuranone
  • Ascorbic acid
  • HIF-1α

ASJC Scopus subject areas

  • Biotechnology
  • Analytical Chemistry
  • Biochemistry
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Organic Chemistry

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