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- Title
Mechanism of the natural product moracin-O derived MO-460 and its targeting protein hnRNPA2B1 on HIF-1α inhibition.
- Authors
Soung, Nak-Kyun; Kim, Hye-Min; Asami, Yukihiro; Kim, Dong Hyun; Cho, Yangrae; Naik, Ravi; Jang, Yerin; Jang, Kusic; Han, Ho Jin; Ganipisetti, Srinivas Rao; Cha-Molstad, Hyunjoo; Hwang, Joonsung; Lee, Kyung Ho; Ko, Sung-Kyun; Jang, Jae-Hyuk; Ryoo, In-Ja; Kwon, Yong Tae; Lee, Kyung Sang; Osada, Hiroyuki; Lee, Kyeong
- 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. A synthetic analog of a chemical found in fruit suppresses tumor growth by targeting an RNA-binding protein (hnRNPA2B1) and preventing the production of a pro-cancer regulatory factor. Nak-Kyun Soung from the Korea Research Institute of Bioscience and Biotechnology, Cheongju, South Korea, and coworkers built on their previous discovery that a compound derived from a medicinal plant metabolite can suppress the activity of hypoxia-inducible factor-1α (HIF-1α). This protein, which is involved in many aspects of cancer biology, is activated in the low-oxygen microenvironments found inside tumors. The researchers show that the compound binds to a protein that helps with the conversion of HIF-1α-encoding RNA transcripts into HIF-1α proteins. Liver cancer cells treated with the compound grew slowly and produced less HIF-1α under both normal and low-oxygen culture conditions, highlighting the potential of this anti-cancer strategy.
- Publication
Experimental & Molecular Medicine EMM, 2019, Vol 51, Issue 2, p1
- ISSN
1226-3613
- Publication type
Article
- DOI
10.1038/s12276-018-0200-4