Abstract
Glioblastoma is a highly aggressive brain tumor characterized by high recurrence and poor prognosis. Vitexin has shown activities against esophageal, liver, lung, colorectal, and ovarian cancers; however, there is little knowledge on the activity of vitexin against glioblastoma. This study was therefore designed with aims to examine the effects of vitexin on proliferation, invasion, and apoptosis of human U251 glioblastoma cells and explore the underlying molecular mechanisms using mRNA sequencing and molecular docking. Vitexin was found to inhibit cell proliferation, colony formation, and invasion and promote apoptosis in U251 cells. mRNA sequencing identified 499 differentially expressed genes in vitexin-treated U251 cells relative to controls, including 154 upregulated genes and 345 downregulated genes. Gene ontology (GO) term enrichment analysis revealed that the upregulated genes were most significantly enriched in intrinsic apoptotic signaling pathway and the downregulated genes were most significantly enriched in positive regulation of cell development and positive regulation of locomotion relating to biological processes, endoplasmic reticulum lumen and side of membrane relating to cellular components, and receptor ligand activity and receptor regulator activity relating to molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the upregulated genes were involved in the pathways of transcriptional misregulation in cancer and the downregulated genes were involved in FoxO and JAK/STAT signaling pathways. Western blotting assay revealed that vitexin treatment resulted in reduced p-JAK1, p-JAK3, and p-STAT3 protein expression in U251 cells relative to untreated controls, and molecular docking predicted that vitexin had docking scores of –8.8, –10.8, and –10.5 kJ/mol with STAT3, JAK1, and JAK2, respectively. The results of the present study demonstrate that vitexin inhibits the proliferation and invasion and induces the apoptosis of glioblastoma U251 cells through suppressing the JAK/STAT3 signaling pathway, and vitexin may be a promising potential agent for the chemotherapy of glioblastoma.
Highlights
Glioma is the most common and the most deadly primary intracranial tumor, representing approximately 80% of all malignant tumors in the central nervous system [1]
Previous studies have shown that vitexin suppresses the growth of esophageal, liver, lung, colorectal, and ovarian cancers [12, 13], and vitexin was found to inhibit the cell viability in a dose- and time-dependent manner and induce G2/M cell cycle arrest and apoptosis by inhibiting Akt/mTOR signaling in human glioblastoma LN-18 cells, suggesting that vitexin may serve as a therapeutic agent for treatment of malignant glioblastoma [14]
Glioma stem cells were reported to activate the STAT3 signaling through secreting IL-6 and IL-10, thereby resulting in activation of B7-H4 expression in tumor-associated macrophages [30], while B7-H4 triggered the escape of glioma-initiating cells from immune surveillance in the microenvironment of gliomas through blocking effective T-cell immune responses [31], indicating that STAT3 is involved in immune escape of gliomas and promotes glioma progression
Summary
Glioma is the most common and the most deadly primary intracranial tumor, representing approximately 80% of all malignant tumors in the central nervous system [1]. There is no cure for glioblastoma multiforme, and the treatment of this highly aggressive malignancy includes conventional surgical resection, radiotherapy, chemotherapy with temozolomide, or bevacizumab, as well as emerging gene therapy and immunotherapy; the overall response. A search for highly effective and lowly toxic agents is of urgent need and of great significance to improve the prognosis among patients with glioblastoma multiforme [8]. This study was designed with aims to examine the effects of vitexin on biological behaviors of human U251 glioblastoma cells and explore the underlying mechanisms using mRNA sequencing and molecular docking, so as to provide insights into the development of novel agents for the treatment of glioblastoma multiforme
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