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Study on the mechanism of Cortex Lycii on lung cancer based on network pharmacology combined with experimental
Zhenhui Guo1, Heng Yin1, Tong Wu2
1Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
Ethnopharmacological Relevance:
Xie Bai San is a Chinese medicine prescription that has been used to treat lung cancer in China for a long time. It has been proven to alleviate the symptoms and extend the survival time of lung cancer patients. Xie Bai San comprises Cortex Lycii, Cortex Mori, and Radix Glycyrrhizae Preparata. The effects and mechanisms of Cortex Mori and Glycyrrhizae on lung cancer have been reported, whereas the underlying mechanism of Cortex Lycii remains unknown.
Material And Methods:
Network pharmacology was used to explore the unknown mechanisms underlying the effect of Cortex Lycii on lung cancer. Molecular docking was used to predict the binding of a compound to the protein. The fingerprint of Cortex Lycii was obtained by HPLC. Cell counting Kit-8 assay was used to determine the appropriate concentration of Cortex Lycii extract for human lung adenocarcinoma cells, A549 and H1299. Wound healing assay and Matrigel invasion assay were used to detect the influence of Cortex Lycii extract on the migration and invasion ability of A549 and H1299. The protein expression level was detected by western blot and immunohistochemical staining.
Results:
Using network pharmacology, 38 components of Cortex Lycii and 79 possible lung cancer-related target genes of Cortex Lycii were obtained. The targets were assigned to 35 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and the PI3K-AKT signaling pathway contained the most targets and had the second-lowest P-value. The molecular docking showed the components of Cortex Lycii bound to HSP90AB1. Among them, 6 components bound to HSP90AB1 in which HSP90AB1 binds to and phosphorylates AKT. The functional experiments showed that Cortex Lycii suppressed the migration and invasion of human lung cancer cells in a dose-dependent manner. Cortex Lycii up-regulated E-Cadherin and down-regulated N-Cadherin, Vimentin, and MMP2. Furthermore, Cortex Lycii made no change in the total AKT and mTOR protein levels, but caused the down-regulation of p-AKT and p-mTOR in human lung cancer cells, which was reversed by Terazosin, an agonist of HSP90. Moreover, acacetin and apigenin, two components of Cortex Lycii, reduced the protein level of p-AKT and p-mTOR, and the reduction was also inhibited by Terazosin.
Conclusion:
Cortex Lycii suppressed epithelial-mesenchymal transition (EMT) in lung cancer cells through the PI3K-AKT-mTOR signaling pathway, possibly by targeting HSP90AB1 and inhibiting HSP90AB1-AKT binding.
