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.
Highlights
Rapid proliferation of cells in solid tumors causes varying degrees of hypoxia in living tissue[1]
Affinity capture reveals hnRNPA2B1 as target of MO-460 To determine the inhibitory mechanisms of MO-460, we synthesized MO-460 (Fig. 1a) as the derivatives of Moracin-O which was reported previously[15], and note that MO-460 inhibits the accumulation of Hypoxia-inducible factor-1α (HIF-1α) protein under cobalt chloride (CoCl2)derived mimetic hypoxic conditions in a concentrationdependent manner (Fig. 1b and c)
We selected 12 protein candidates with the highest affinities for MO-460 (Table 1 and Supplementary Figure S1b), and inhibited their expression using siRNA to determine their effects on hypoxia-inducible factor (HIF)-1α accumulation in the nuclei under mimetic hypoxia (Fig. 1d and Supplementary Figure S2a)
Summary
Rapid proliferation of cells in solid tumors causes varying degrees of hypoxia in living tissue[1]. Cancer cells under hypoxic conditions accumulate a range of proteins through transcriptional induction, which promotes the growth of tumor tissue and provides resistance to cell death. These proteins play critical roles in angiogenesis, cell proliferation, glucose uptake, apoptosis, and metastasis[2,3,4]. The presence of active HIF-1α and subsequent induction of its downstream genes promote cancer cell resistance to chemotherapy through various cellular responses (e.g., suppressing apoptosis[5], bypassing senescence[6,7], altering cellular metabolism[8], increasing drug efflux[9]). The inhibition of HIF-1α activity has attracted considerable interest by those looking to develop efficient therapeutic strategies for various solid cancers
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