4-O-methylascochlorin stabilizes hypoxia-inducible factor-1 in a manner different from hydroxylase inhibition by iron chelating or substrate competition.
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| 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.
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| Authors | Junji Magae, Chiharu Furukawa, Shigefumi Kuwahara, Yun-Jeong Jeong, Hiroo Nakajima, Young-Chae Chang |
| Journal | Bioscience, biotechnology, and biochemistry (Biosci Biotechnol Biochem) Vol. 83 Issue 12 Pg. 2244-2248 (Dec 2019) ISSN: 1347-6947 [Electronic] England |
| PMID | 31392931 (Publication Type: Journal Article) |
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