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KMID : 0620920190510020010
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Experimental & Molecular Medicine
2019 Volume.51 No. 2 p.10 ~ p.10
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Mechanism of the natural product moracin-O derived MO-460 and its targeting protein hnRNPA2B1 on HIF-1α inhibition
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Soung Nak-Kyun
Kim Hye-Min
Asami Yukihiro
Kim Dong-Hyun
Cho Yang-Rae
Naik Ravi
Jang Ye-Rin
Jang Ku-Sic
Han Ho-Jin
Ganipisetti Srinivas Rao
Cha-Molstad Hyun-Joo
Hwang Joon-Sung
Lee Kyung-Ho
Ko Sung-Kyun
Jang Jae-Hyuk
Ryoo In-Ja
Kwon Yong-Tae
Lee Kyung-Sang
Osada Hiroyuki
Lee Kyeong
Kim Bo-Yeon
Ahn Jong-Seog
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Abstract
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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.
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KEYWORD
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Targeted therapies
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