Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, 030006, China.
Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):467-480. doi: 10.1007/s00210-018-1585-2. Epub 2018 Dec 17.
Glucose-regulated protein 78 (GRP78) often highly expresses in a wide range of tumors, which plays promotive functions due to its diversity of location in the development of tumor. Particularly, GRP78 can be secreted into microenvironment by tumor cells through the pathway of exosome, which promotes proliferation, angiogenesis, and drug resistance in cancer cells. Hence, we discovered a potential inhibitor to block GRP78 secretion. We screened five small molecules that may interact with the GRP78 from 51 traditional Chinese medicine molecules by molecular docking. By using western blot, we found that one of the molecules can inhibit the secretion of GRP78, which is salvianolic acid A (SAA). Further, SAA could interact with the lysine residue 633 (K633) of GRP78, which inhibited GRP78 secretion. Moreover, SAA-GRP78 interaction can facilitate GRP78 of cytosol sorted into lysosome for degradation rather than exosome. In conclusion, our research revealed that SAA has the novel function of anti-angiogenesis via the tumor environment.
葡萄糖调节蛋白 78（GRP78）在广泛的肿瘤中常常高度表达，由于其在肿瘤发展中的位置多样性，发挥着促进作用。特别是，GRP78 可以通过外泌体途径被肿瘤细胞分泌到微环境中，促进癌细胞的增殖、血管生成和耐药性。因此，我们发现了一种潜在的抑制剂来阻断 GRP78 的分泌。我们通过分子对接从 51 种中药分子中筛选了可能与 GRP78 相互作用的 5 种小分子。通过 Western blot，我们发现其中一种分子可以抑制 GRP78 的分泌，即丹酚酸 A（SAA）。进一步研究发现，SAA 可以与 GRP78 的赖氨酸残基 633（K633）相互作用，从而抑制 GRP78 的分泌。此外，SAA-GRP78 相互作用可以促进细胞质中的 GRP78 分选到溶酶体进行降解，而不是外泌体。总之，我们的研究揭示了 SAA 通过肿瘤微环境具有抑制血管生成的新功能。
