Mechanism of the natural product moracin-O derived MO-460 and its targeting protein hnRNPA2B1 on HIF-1α inhibition

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Title
Mechanism of the natural product moracin-O derived MO-460 and its targeting protein hnRNPA2B1 on HIF-1α inhibition
Author(s)
Nak Kyun Soung; Hye-Min Kim; Y Asami; Dong Hyun Kim; Yangrae Cho; R Naik; Y Jang; K Jang; H J Han; S R Ganipisetti; Hyunjoo ChaJoonsung HwangKyung Ho LeeSung-Kyun KoJae-Hyuk JangIn Ja Ryoo; Y T Kwon; K S Lee; H Osada; K Lee; Bo Yeon KimJong Seog Ahn
Bibliographic Citation
Experimental and Molecular Medicine, vol. 51, no. 2, pp. 10-10
Publication Year
2019
Abstract
Hypoxia-inducible factor-1α (HIF-1α) mediates tumor cell adaptation to hypoxic conditions and is a potentially important anticancer therapeutic target. We previously developed a method for synthesizing a benzofuran-based natural product, (R)-(-)-moracin-O, and obtained a novel potent analog, MO-460 that suppresses the accumulation of HIF-1α in Hep3B cells. However, the molecular target and underlying mechanism of action of MO-460 remained unclear. In the current study, we identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a molecular target of MO-460. MO-460 inhibits the initiation of HIF-1α translation by binding to the C-terminal glycine-rich domain of hnRNPA2B1 and inhibiting its subsequent binding to the 3'-untranslated region of HIF-1α mRNA. Moreover, MO-460 suppresses HIF-1α protein synthesis under hypoxic conditions and induces the accumulation of stress granules. The data provided here suggest that hnRNPA2B1 serves as a crucial molecular target in hypoxia-induced tumor survival and thus offer an avenue for the development of novel anticancer therapies.
ISSN
I000-0028
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s12276-018-0200-4
Type
Article
Appears in Collections:
Ochang Branch Institute > Anticancer Agent Research Center > 1. Journal Articles
Ochang Branch Institute > Natural Medicine Research Center > 1. Journal Articles
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