The 20S ginsenoside Rh2 (G-Rh2) effectively inhibits cancer cell growth and survival in both animal models and cell lines. However, its molecular targets and mechanism of action remain largely unknown. By screening for molecules that interact with (20S)G-Rh2 in a phage display assay, we have identified Annexin A2 as a potential target that mediates its anti-cancer activity. Isothermal titration calorimetry and a cellular thermal shift assay demonstrated that (20S)G-Rh2 directly bound to either recombinant or intracellular Annexin A2. This binding inhibited the interaction between Annexin A2 and the NF-кB p50 subunit, which attenuated the nuclear translocations of NF-кB p50 subunit and reduced the transactivation activity of NF-кB. Correspond to this result, (20S)G-Rh2 treatment significantly down-regulated the expression of IAPs (inhibitors of apoptosis), the well-established NF-кB targets that promote cell survival. Moreover, (20S)G-Rh2 synergized with Annexin A2 inactivation to promote apoptosis. Taken together, this study for the first time suggests a cellular target and a molecular pathway by which (20S)G-Rh2 inhibits cancer cell growth. As over-expression of Annexin A2 was evident in human hepatoma, (20S)G-Rh2 might be a promising natural compound for targeted liver cancer therapy.

中文翻译：

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（20S）人参皂甙Rh2的抗癌活性分子靶标的鉴定。

20S人参皂苷Rh2（G-Rh2）在动物模型和细胞系中均能有效抑制癌细胞的生长和存活。但是，其分子靶标和作用机理仍然未知。通过在噬菌体展示试验中筛选与（20S）G-Rh2相互作用的分子，我们已经鉴定出膜联蛋白A2是介导其抗癌活性的潜在靶标。等温滴定热法和细胞热位移分析表明（20S）G Rh2直接绑定到重组或细胞内膜联蛋白A2。这种结合抑制膜联蛋白A2和NF-кBp50亚基之间的相互作用，从而减弱了NF-кBp50亚基的核易位并降低了NF-кB的反式激活活性。对应于这个结果，（20S）G-Rh2处理显着下调了IAPs（凋亡抑制剂）的表达，IAPs是成熟的促进细胞存活的NF-кB靶标。而且，（20S）G-Rh2与膜联蛋白A2失活协同作用以促进细胞凋亡。两者合计，这项研究首次建议（20S）G-Rh2抑制癌细胞生长的细胞靶标和分子途径。由于膜联蛋白A2的过表达在人肝癌中很明显，（20S）G-Rh2可能是靶向肝癌治疗的有希望的天然化合物。