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 language | English |
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Pages (from-to) | 2244-2248 |
Number of pages | 5 |
Journal | Bioscience, Biotechnology and Biochemistry |
Volume | 83 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2019 |
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