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

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2019-12, Vol.83 (12), p.2244-2248
• Main Authors: Magae, Junji, Furukawa, Chiharu, Kuwahara, Shigefumi, Jeong, Yun-Jeong, Nakajima, Hiroo, Chang, Young-Chae
• Format: Article
• Language: English
• Subjects: 4-O-methylascochlorin; Ascochlorin; ascofuranone; ascorbic acid; Binding, Competitive; Cell Line, Tumor; HIF-1α; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - drug effects; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Iron Chelating Agents - pharmacology; Mixed Function Oxygenases - metabolism; Structure-Activity Relationship; Substrate Specificity; Terpenes - chemistry; Terpenes - pharmacology
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1080/09168451.2019.1651626

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. Ascochlorin-related compounds activate the HIF-1 transcription factor in a manner distinct from known activators.