Exploring the Mechanism of Sempervirine Inhibiting Glioblastoma Invasion Based on Network Pharmacology and Bioinformatics

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2024 Oct 26

PMID 39458959

Authors

Bingqiang Zhang

Wenyi Wang

Yu Song

Huixian Chen

Xinxin Lin

Jingjing Chen

Ying Chen

Jinfang Huang

Desen Li

Shuisheng Wu

Affiliations

Soon will be listed here.

Abstract

: Invasion is an important characteristic of the malignancy of glioblastoma (GBM) and a significant prognostic factor. Sempervirine (SPV), a yohimbine-type alkaloid, has been proven to inhibit GBM cells proliferation in previous research and found to have a potential effect in anti-invasion, but its mechanism of anti-invasion is still unknown. : To explore its pharmacodynamics in inhibiting GBM cell invasion in this study, we combined network pharmacology and bioinformatics to comprehensive exploratory analysis of SPV and verified the mechanism in vitro. : Firstly, targets of SPV and invasion-related genes were collected from public databases. Moreover, GBM samples were obtained to analyze differentially expressed genes (DEGs) from The Cancer Genome Atlas (TCGA). Then, the relevant targets of SPV inhibiting GBM invasion (SIGI) were obtained through the intersection of the three gene sets. Further, GO and KEGG analysis showed that the targets of SIGI were heavily enriched in the AKT signaling pathway. Subsequently, based on the method of machine learning, a clinical prognostic model of the relevant targets of SIGI was constructed using GBM samples from TCGA and the Gene Expression Omnibus (GEO). A four-genes model (, , , and ) was successfully constructed, and Vina Scores of MMP2 and MMP13 in molecular docking were higher, which may be the main targets of SIGI. Then, the effect of SIGI was confirmed via functional experiments on invasion, migration, and adhesion assay, and the effect involved changes in the expressions of p-AKT, MMP2 and MMP13. Finally, combined with AKT activator (SC79) and inhibitor (MK2206), we further confirmed that SPV inhibits GBM invasion through AKT phosphorylation. : This study provides valuable and an expected point of view into the regulation of AKT phosphorylation and inhibition of GBM invasion by SPV.

References

Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X . PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017; 45(W1):W356-W360. PMC: 5793840. DOI: 10.1093/nar/gkx374. View

Gao H, Lin S, Han X, Xu H, Gao Y, Qin Z . Casein kinase 1 (CK1) promotes the proliferation and metastasis of glioma cells via the phosphatidylinositol 3 kinase-matrix metalloproteinase 2 (AKT-MMP2) pathway. Ann Transl Med. 2021; 9(8):659. PMC: 8106055. DOI: 10.21037/atm-21-935. View

Touw W, Baakman C, Black J, Te Beek T, Krieger E, Joosten R . A series of PDB-related databanks for everyday needs. Nucleic Acids Res. 2014; 43(Database issue):D364-8. PMC: 4383885. DOI: 10.1093/nar/gku1028. View

Liu Y, Yang X, Gan J, Chen S, Xiao Z, Cao Y . CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Res. 2022; 50(W1):W159-W164. PMC: 9252749. DOI: 10.1093/nar/gkac394. View

Guan N, Huo X, Zhang Z, Zhang S, Luo J, Guo W . Ginsenoside Rh2 inhibits metastasis of glioblastoma multiforme through Akt-regulated MMP13. Tumour Biol. 2015; 36(9):6789-95. DOI: 10.1007/s13277-015-3387-1. View

Wishart D, Feunang Y, Guo A, Lo E, Marcu A, Grant J . DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017; 46(D1):D1074-D1082. PMC: 5753335. DOI: 10.1093/nar/gkx1037. View

Kim S, Thiessen P, Bolton E, Chen J, Fu G, Gindulyte A . PubChem Substance and Compound databases. Nucleic Acids Res. 2015; 44(D1):D1202-13. PMC: 4702940. DOI: 10.1093/nar/gkv951. View

Zepecki J, Snyder K, Moreno M, Fajardo E, Fiser A, Ness J . Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor. Oncogene. 2018; 38(10):1734-1750. PMC: 6462869. DOI: 10.1038/s41388-018-0546-z. View

Wang Z, Jensen M, Zenklusen J . A Practical Guide to The Cancer Genome Atlas (TCGA). Methods Mol Biol. 2016; 1418:111-41. DOI: 10.1007/978-1-4939-3578-9_6. View

10.

Sherman B, Hao M, Qiu J, Jiao X, Baseler M, Lane H . DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022; 50(W1):W216-W221. PMC: 9252805. DOI: 10.1093/nar/gkac194. View

11.

Varela M, Comba A, Faisal S, Argento A, Franson A, Barissi M . Gene Therapy for High Grade Glioma: The Clinical Experience. Expert Opin Biol Ther. 2022; 23(2):145-161. PMC: 9998375. DOI: 10.1080/14712598.2022.2157718. View

12.

Jain R . Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng. 2001; 1:241-63. DOI: 10.1146/annurev.bioeng.1.1.241. View

13.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

14.

Shao Y, Zhang T, Wu L, Zou H, Li S, Huang J . AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells. Int J Mol Sci. 2017; 18(2). PMC: 5343885. DOI: 10.3390/ijms18020350. View

15.

Zhang Z, Lu M, Liu Z, Li H, Yong Y, Zhang R . Rab11a regulates MMP2 expression by activating the PI3K/AKT pathway in human hepatocellular carcinoma cells. Pathol Res Pract. 2020; 216(9):153046. DOI: 10.1016/j.prp.2020.153046. View

16.

Tan A, Ashley D, Lopez G, Malinzak M, Friedman H, Khasraw M . Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020; 70(4):299-312. DOI: 10.3322/caac.21613. View

17.

Oishi T, Koizumi S, Kurozumi K . Molecular Mechanisms and Clinical Challenges of Glioma Invasion. Brain Sci. 2022; 12(2). PMC: 8870089. DOI: 10.3390/brainsci12020291. View

18.

Lee H, Tsygankov A . c-Cbl regulates glioma invasion through matrix metalloproteinase 2. J Cell Biochem. 2010; 111(5):1169-78. DOI: 10.1002/jcb.22839. View

19.

Amberger J, Bocchini C, Schiettecatte F, Scott A, Hamosh A . OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 2014; 43(Database issue):D789-98. PMC: 4383985. DOI: 10.1093/nar/gku1205. View

20.

Sayers E, Bolton E, Brister J, Canese K, Chan J, Comeau D . Database resources of the National Center for Biotechnology Information in 2023. Nucleic Acids Res. 2022; 51(D1):D29-D38. PMC: 9825438. DOI: 10.1093/nar/gkac1032. View