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.

中文翻译：

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天然产物moracin-O衍生的MO-460及其靶向蛋白hnRNPA2B1抑制HIF-1α的机制。

缺氧诱导因子-1α（HIF-1α）介导肿瘤细胞适应缺氧条件，是潜在的重要抗癌治疗靶点。我们之前开发了一种合成基于苯并呋喃的天然产物 (R)-(-)-moracin-O 的方法，并获得了一种新的有效类似物 MO-460，可抑制 HIF-1α 在 Hep3B 细胞中的积累。然而，MO-460的分子靶点和潜在作用机制仍不清楚。在目前的研究中，我们将异质核核糖核蛋白 A2B1 (hnRNPA2B1) 鉴定为 MO-460 的分子靶标。MO-460 通过与 hnRNPA2B1 的 C 末端富含甘氨酸的结构域结合并抑制其随后与 HIF-1α mRNA 的 3'-非翻译区的结合来抑制 HIF-1α 翻译的启动。而且，MO-460 在缺氧条件下抑制 HIF-1α 蛋白合成并诱导应激颗粒的积累。此处提供的数据表明，hnRNPA2B1 是缺氧诱导的肿瘤存活中的关键分子靶标，因此为开发新型抗癌疗法提供了途径。