scholarly journals Network Pharmacology-Based Prediction and Verification of the Mechanism of Shikonin in the Treatment of Colorectal Cancer

2021 ◽  
Author(s):  
Zefeng Wang ◽  
Qianfei Cui ◽  
Ling Shi ◽  
Xiaojing Lu ◽  
Yongjia Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Akt Signaling ◽  
Venn Diagram ◽  
Migration And Invasion ◽  
Network Pharmacology ◽  
Akt Signaling Pathway ◽  
Pathway Network ◽  
Pharmacological Analysis

Abstract Background: Zicao is the dried root of Lithospermum erythrorhizon Sieb, et Zucc, Arnebia euchroma (Royle) Johnst, or Arnebia guttata Bunge and is commonly used to treat viral infection, inflammation, arthritis, and cancer in traditional Chinese medicine. Shikonin (SKN), a naturally occurring naphthoquinone, is a major active chemical component isolated from Zicao and exhibits anticancer activity according to previous research. However, the underlying mechanism has not been elucidated, so further research is necessary to verify its traditional application. The purpose of the present study was to investigate the antitumor mechanism of SKN in colorectal cancer (CRC) through network pharmacology and experiments.Methods: The SymMap database and GeneCards were adopted to predict the potential targets of SKN and CRC, while cotargets were obtained via a Venn diagram. The cotargets were imported from the String and DAVID websites, the protein-protein interaction (PPI) network was constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. With regard to the prediction of KEGG by DAVID, the compound-target-pathway network was generated by connecting potential pathways with the corresponding targets. According to the network pharmacological analysis, cytological experiments, real-time PCR (RT-PCR), and Western blot (WB) were used to verify the key signaling pathway.Results: According to the network pharmacological analysis, the most relevant target of SKN to the treatment of colorectal cancer was IL6. GO and KEGG enrichment analyses indicated that various kinases and the PI3K/AKT signaling pathway were the most enriched molecules and pathways. SKN inhibited CRC cell (HT29 and HCT116) proliferation, migration, and invasion and promoted cell apoptosis by targeting IL6 and inhibiting the IL6R/PI3K/AKT signaling pathway.Conclusions: SKN promotes apoptosis and suppresses CRC cell (HT29 and HCT116) activities through the PI3K-Akt signaling pathway. This research not only provides a theoretical and experimental basis for more in-depth studies but also offers an efficient method for the rational utilization of a series of traditional Chinese medicines as anti-CRC drugs.

Network Pharmacology-Based Prediction and Verification of Shikonin for the mechanism treating colorectal cancer

2021 ◽  
Vol 17 ◽  
Author(s):  
Zefeng Wang ◽  
Qianfei Cui ◽  
Ling Shi ◽  
Meiling Zhang ◽  
Peng Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Akt Signaling ◽  
Venn Diagram ◽  
Migration And Invasion ◽  
Network Pharmacology ◽  
Akt Signaling Pathway ◽  
Protein Protein Interaction ◽  
Arnebia Euchroma

Background: Shikonin (SKN), a naturally occurring naphthoquinone, is a major active chemical component isolated from Lithospermum erythrorhizon Sieb Zucc, Arnebia euchroma (Royle) Johnst, or Arnebia guttata Bunge, and commonly used to treat viral infection, inflammation, and cancer. However, the underlying mechanism has not been elucidated Objective: This study aims to explore the antitumor mechanism of SKN in colorectal cancer (CRC) through network pharmacology and cell experiments. Methods: Using SymMap database and Genecards to predict the potential targets of SKN and CRC, while the cotargets were obtained by Venn diagram. The cotargets were imported into website of String and DA DAVID, constructing the protein-protein interaction (PPI) network, performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, the Compound-Target-Pathway (C-T-P) network was generated by connecting potential pathways with the corresponding targets. Results: According to the results of network pharmacological analysis, the cell experiments were used to verify the key signal pathway. The most relevant target of SKN for the treatment of CRC was PI3K/Akt signaling pathway. SKN inhibited CRC cells (HT29 and HCT116) proliferation, migration, and invasion, and promoted cell apoptosis by targeting IL6 and inhibiting the IL6R/PI3K/Akt signaling pathway. SKN promotes apoptosis and suppresses CRC cells (HT29 and HCT116) activity through the PI3K-Akt signaling pathway. Conclusion: This research not only provides a theoretical and experimental basis for more in-depth studies but also offers an efficient method for the rational utilization of a series of Traditional Chinese medicines as anti-CRC drugs.

scholarly journals CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Tao Jiang ◽  
Hongyu Wang ◽  
Lianyu Liu ◽  
Hu Song ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
In Situ Hybridization ◽  
Signaling Pathway ◽  
Clinical Significance ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Aberrant Expression

Abstract Background Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored. Methods CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT–PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R. Results CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression. Conclusions Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.

scholarly journals CORO1C is Associated With Poor Prognosis and Promotes Metastasis Through PI3K/AKT Pathway in Colorectal Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Zongxia Wang ◽  
Lizhou Jia ◽  
Yushu sun ◽  
Chunli Li ◽  
Lingli Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Poor Prognosis ◽  
Akt Signaling ◽  
Actin Binding ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Related Proteins

Trophoblast cell surface protein 2 (Trop2) is one of the cancer-related proteins that plays a vital role in biological aggressiveness and poor prognosis of colorectal cancer (CRC). The study of the Trop2 related network is helpful for us to understand the mechanism of tumorigenesis. However, the effects of the related proteins interacting with Trop2 in CRC remain unclear. Here, we found that coronin-like actin-binding protein 1C (CORO1C) could interact with Trop2 and the expression of CORO1C in CRC tissues was higher than that in paracarcinoma tissues. The expression of CORO1C was associated with histological type, lymph node metastasis, distant metastasis, AJCC stage, venous invasion, and perineural invasion. The correlation between CORO1C expression and clinical characteristics was analyzed demonstrating that high CORO1C expression in CRC patients were associated with poor prognosis. Furthermore, CORO1C knockdown could decrease the cell proliferation, colony formation, migration and invasion in vitro and tumor growth in vivo. The underlying mechanisms were predicted by bioinformatics analysis and verified by Western blotting. We found that PI3K/AKT signaling pathway was significantly inhibited by CORO1C knockdown and the tuomr-promoting role of CORO1C was leastwise partly mediated by PI3K/AKT signaling pathway. Thus, CORO1C may be a valuable prognostic biomarker and drug target in CRC patients.

scholarly journals Network Pharmacology-Based Study to Uncover Potential Pharmacological Mechanisms of Korean Thistle (Cirsium japonicum var. maackii (Maxim.) Matsum.) Flower against Cancer

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5904
Author(s):  
Ki-Kwang Oh ◽  
Md. Adnan ◽  
Dong-Ha Cho
Keyword(s):  
Methyl Ester ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Venn Diagram ◽  
Network Pharmacology ◽  
Akt Signaling Pathway ◽  
Anti Cancer ◽  
Cirsium Japonicum ◽  
Folk Remedies

Cirsium japonicum var. maackii (Maxim.) Matsum. or Korean thistle flower is a herbal plant used to treat tumors in Korean folk remedies, but its essential bioactives and pharmacological mechanisms against cancer have remained unexplored. This study identified the main compounds(s) and mechanism(s) of the C. maackii flower against cancer via network pharmacology. The bioactives from the C. maackii flower were revealed by gas chromatography-mass spectrum (GC-MS), and SwissADME evaluated their physicochemical properties. Next, target(s) associated with the obtained bioactives or cancer-related targets were retrieved by public databases, and the Venn diagram selected the overlapping targets. The networks between overlapping targets and bioactives were visualized, constructed, and analyzed by RPackage. Finally, we implemented a molecular docking test (MDT) to explore key target(s) and compound(s) on AutoDockVina and LigPlot+. GC-MS detected a total of 34 bioactives and all were accepted by Lipinski’s rules and therefore classified as drug-like compounds (DLCs). A total of 597 bioactive-related targets and 4245 cancer-related targets were identified from public databases. The final 51 overlapping targets were selected between the bioactive targets network and cancer-related targets. With Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, a total of 20 signaling pathways were manifested, and a hub signaling pathway (PI3K-Akt signaling pathway), a key target (Akt1), and a key compound (Urs-12-en-24-oic acid, 3-oxo, methyl ester) were selected among the 20 signaling pathways via MDT. Overall, Urs-12-en-24-oic acid, 3-oxo, methyl ester from the C. maackii flower has potent anti-cancer efficacy by inactivating Akt1 on the PI3K-Akt signaling pathway.

scholarly journals Girdin regulates the migration and invasion of glioma cells via the PI3K-Akt signaling pathway

2015 ◽  
Vol 12 (4) ◽  
pp. 5086-5092 ◽  
Author(s):  
WEIMIN NI ◽  
YAN FANG ◽  
LEI TONG ◽  
ZHAOXUE TONG ◽  
FUXIN YI ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glioma Cells ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway
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