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제118회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Identification of Cellular Target for the Synthetic Analogue of Natural Product Regulating HIF-1α Expression

2016년 9월 1일 15시 25분 08초
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금 09시 : 35분
생명화학 - Frontiers in Chemical Biology
저자 및
한국생명공학연구원 항암물질연구단, Korea
Rapid proliferation of cells in solid tumors causes various extents of hypoxia, oxygen-deprived states in the tissue. Cancer cells under hypoxia accumulate a gamut of proteins via transcriptional induction, which supports growth of tumor tissues and promotes resistance to cell death. These proteins play critical roles in controlling angiogenesis, cell proliferation, glucose uptake, apoptosis, and metastasis. The transcriptional induction of these genes is mediated by the master regulator of transcription factor, hypoxia-inducible factor (HIF)-1, which results in selection of cancer cells that are adapted to hypoxic conditions. HIF-1 is a heterodimeric protein composed of HIF-1α and HIF-1β subunits. The alpha subunit is continuously transcribed and translated, and its stability is regulated by oxygen level. The activity of HIF-1 is regulated by the stability of the alpha subunit that accumulates under hypoxia but is rapidly degraded unlike the beta subunit under normoxia. The accumulation of HIF-1α is prerequisite condition for the activity of HIF-1, which has become an important cancer therapeutic target.
Moracin O with an arylbenzofuran ring isolated from Morus species is a natural product and it exerts potent inhibitory effect on HIF-1 accumulation under a hypoxic condition. The exact molecular target or underlying mechanism of moracin remains unknown, which is bottleneck for further development of moracin as novel anticancer agent. Synthetic methodology for moracin previously developed and a novel and potent analogue obtained which potently suppressed hypoxia-induced HIF-1α accumulation in Hep3B cells. Accordingly using a synthetic derivative, we identified its molecular target and subsequently elucidated its role in HIF-1α accumulation through an affinity capture method followed by identification of putative target proteins by mass spectrometry, chemical-protein binding assay and various biological assays.