Network Pharmacology-Based Study on the Mechanism of Ginsenoside Rh2 in Glioma Treatment

Abstract

Glioma, originated from the neuroectoderm, is one of the prevalent tumors. It is reported that ginsenoside Rh2, a compound extracted from Panax ginseng, shows pharmacological activity in inhibiting the proliferation and metastasis of glioma cells. However, the precise underlying mechanism has not been completely clarified. In this study, the molecular mechanism of ginsenoside Rh2 in glioma treatment was investigated using network pharmacology, through which the target of ginsenoside Rh2 in glioma treatment was screened, and further the biological functions were analyzed by gene ontology biological annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. In total, 80 potential targets of ginsenoside Rh2 for glioma treatment were screened. Biological functions analysis revealed that ginsenoside Rh2 was associated with several cancer-related signaling pathways such as VEGF signaling pathway, thereby regulating cell processes, including cell migration and cell proliferation, which suggests that ginsenoside Rh2 targets multiple genes, further mediating indicated signaling network in anti-glioma and providing a potential mechanism of ginsenoside Rh2 in glioma treatment.

Keywords

network pharmacology ginsenoside Rh2 glioma GO enrichment KEGG pathway

Introduction

Glioma originates from the neuroectoderm and is a common intracranial malignancy, with the characteristics of malignancy and metastasis.^1,2 The clinical treatment of glioma mainly involves surgery, combined with radiotherapy and chemotherapy as an adjuvant therapy.³ Compounds derived from natural products, especially traditional herbs, show multiple activities such as anti-inflammatory, immune stimulating, and anti-cancer.⁴

Ginsenoside Rh2, one of the active ingredients of Panax ginseng, has been identified as a bioactive effect in inhibiting the proliferation (in vivo and in vitro) as well as metastasis of glioma.^5‐7 In detail, ginsenoside Rh2 suppresses the viability of U251 glioma cells via targeting microRNA-128,⁵ arresting the cell cycle of A172 glioma cells at G1 phase by inhibiting the expression of cyclin-dependent kinase (CDK4) and cyclin D.⁸ Moreover, ginsenoside Rh2 inhibits the expression of matrix metallopeptidase-13 (MMP13), which, mediated by the phosphatidylinositol-3-kinase (PI3K)/Akt (PI3k/Akt) signaling pathway, further blocks U251 glioma cells migration.⁵ However, the mechanism of ginsenoside Rh2 inhibiting glioma progression has not been completely clarified.

In this study, via network pharmacology, the targets of glioma and ginsenoside Rh2 were screened respectively, and further the potential molecular mechanisms of ginsenoside Rh2 in glioma treatment were analyzed. Through this, we propose to provide thoughts and foundation for the future ginsenoside Rh2–glioma research.

Materials and Methods

Prediction of Target of Ginsenoside Rh2

The term “ginsenoside Rh2” was searched for in the PubChem database; the SMILES number for ginsenoside Rh2 (CC( = CCCC(C)(C1CCC2(C1C(CC3C2(CCC4C3(CCC(C4(C)C)OC5C(C(C(C(O5)CO)O)O)O)C)C)O)C)O)C) was obtained, which was used in a SwissTargetPrediction database search to obtain the candidate target of the active ingredient.

Screening of Glioma Target Proteins

Glioma target proteins were obtained by searching for the keywords “glioma” and “nervglioma” in GeneCards, Therapeutic Target Database (TTD), and Online Mendelian Inheritance in Man (OMIM); the species Homo sapiens (human) was selected in the UniProt database. Gene names and UniProt numbers of target proteins were obtained.

Construction of the Component–Target Network

The obtained components and disease targets were sorted, deduplicated, and mapped to obtain the intersection genes and draw the Venn diagram. Cytoscape 3.2.1 was used to visualize the network of the intersection proteins, and a “component-target” network of ginsenoside Rh2 and the target for glioma treatment were constructed.

Construction of the Protein–Protein Interaction Network

The “Multiple Proteins” function of the STRING database (https://string-db.org) was used, the species was set as human (Homo sapiens), the protein target of ginsenoside Rh2 intervention in glioma was imported into the system, and the score value was set to > 0.900 to search for and draw a protein–protein interaction network.

Analysis of Gene Ontology Biological Function and KEGG Pathway Enrichment

The ginsenoside Rh2 intervention gene for glioma was input into the Database for Annotation, Visualization and Integrated Discovery (DAVID). The species was set as human (Homo sapiens), and the biological process, molecular function, and cell component categories were selected for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses.

Results

Prediction and Interaction of Ginsenoside Rh2–-Glioma Targets

Through searching indicated databases, combined with sorting and deduplicating, 110 candidate targets of ginsenoside Rh2 were obtained, and 4805 glioma-related genes were collected. As shown in Figure 1A, 80 overlapping genes were obtained, including epidermal growth factor receptor (EFGR), MMP2, CKD4, histone deacetylase 2 (HDAC2), etc. (Figure 1B); the details are listed in Table 1. To identify the interaction between the crossed gene, the STRING database was used to establish a PPI network, including 80 nodes and 128 connections (confidence score > 0.95) (Figure 1C).

Figure 1.

Prediction and interaction of ginsenoside Rh2-glioma targets. (A) Wayne diagram of ginsenoside Rh2 and glioma candidate targets. (B) Ginsenoside Rh2-targeting glioma network. The blue rhombus represents the potential target of ginsenoside Rh2 in the treatment of glioma. (C) The protein-protein interaction (PPI) network. The "node" in the network represents the target protein, and the "edge" represents the interaction between the target proteins. The more the number of edges, the more important the role of the target protein corresponding to the node in the network.

Table 1.

The Therapeutic Targets of Ginsenoside Rh2 in Glioma Treatment.

No.	Gene	Abbreviate	Uniprot Id
1	Epidermal growth factor receptor	EGFR	P00533
2	Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha	PIK3CA	P42336
3	Erb-b2 receptor tyrosine kinase 2	ERBB2	P04626
4	Matrix metallopeptidase 2	MMP2	P08253
5	Platelet-derived growth factor receptor alpha	PDGFRA	P16234
6	Cyclin-dependent kinase 4	CDK4	P11802
7	Vascular endothelial growth factor A	VEGFA	P15692
8	Platelet-derived growth factor receptor beta	PDGFRB	P09619
9	Fibroblast growth factor 2	FGF2	P09038
10	Cyclin-dependent kinase 6	CDK6	Q00534
11	Interleukin-2	IL2	P60568
12	Mitogen-activated protein kinase 14	MAPK14	Q16539
13	Signal transducer and activator of transcription 3	STAT3	P40763
14	Kinase insert domain receptor	KDR	P35968
15	Mitogen-activated protein kinase kinase 1	MAP2K1	Q02750
16	Cyclin-dependent kinase 2	CDK2	P24941
17	KIT proto-oncogene, receptor tyrosine kinase	KIT	P10721
18	Phosphoinositide-3-kinase regulatory subunit 1	PIK3R1	P27986
19	Polo like kinase 1	PLK1	P53350
20	Bcl-2-like 1	BCL2L1	Q07817
21	SRC proto-oncogene, non-receptor tyrosine kinase	SRC	P12931
22	Cyclin-dependent kinase 1	CDK1	P06493
23	Mitogen-activated protein kinase 8	MAPK8	P45983
24	Histone deacetylase 1	HDAC1	Q13547
25	Cathepsin B	CTSB	P07858
26	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma	PIK3CG	P48736
27	ABL proto-oncogene 1, non-receptor tyrosine kinase	ABL1	P00519
28	Checkpoint kinase 1	CHEK1	O14757
29	neurotrophic receptor tyrosine kinase 1	NTRK1	P04629
30	Thymidylate synthase	TYMS	P04818
31	Fibroblast growth factor 1	FGF1	P05230
32	Integrin subunit alpha V	ITGAV	P06756
33	LCK proto-oncogene, Src family tyrosine kinase	LCK	P06239
34	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta	PIK3CB	P42338
35	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta	PIK3CD	O00329
36	Integrin subunit beta 3	ITGB3	P05106
37	Mitogen-activated protein kinase 9	MAPK9	P45984
38	Janus kinase 2	JAK2	O60674
39	Heat shock protein 90 alpha family class A member 1	HSP90AA1	P07900
40	Matrix metallopeptidase 1	MMP1	P03956
41	Cathepsin L	CTSL	P07711
42	Heparanase	HPSE	Q9Y251
43	ADAM metallopeptidase domain 17	ADAM17	P78536
44	Mitogen-activated protein kinase 12	MAPK12	P53778
45	Aurora kinase A	AURKA	O14965
46	Histone deacetylase 3	HDAC3	O15379
47	Dipeptidyl peptidase 4	DPP4	P27487
48	Galectin-3	LGALS3	P17931
49	Adenosine kinase	ADK	P55263
50	Sphingosine-1-phosphate receptor 1	S1PR1	P21453
51	Histone deacetylase 2	HDAC2	Q92769
52	Monoamine oxidase B	MAOB	P27338
53	Matrix metallopeptidase 13	MMP13	P45452
54	Colony stimulating factor 1 receptor	CSF1R	P07333
55	Monoamine oxidase A	MAOA	P21397
56	Histone deacetylase 6	HDAC6	Q9UBN7
57	Arachidonate 5-lipoxygenase-activating protein	ALOX5AP	P20292
58	Nuclear receptor corepressor 2	NCOR2	Q9Y618
59	Presenilin-2	PSEN2	P49810
60	Sphingosine-1-phosphate receptor 1	SCNN1A	P37088
61	Histone deacetylase 7	HDAC7	Q8WUI4
62	6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3	PFKFB3	Q16875
63	Adenosine A1 receptor	ADORA1	P30542
64	Phosphoglycerate kinase 1	PGK1	P00558
65	Histone deacetylase 5	HDAC5	Q9UQL6
66	Nicotinamide phosphoribosyltransferase	NAMPT	P43490
67	Sphingosine-1-phosphate receptor 3	S1PR3	Q99500
68	Platelet-activating factor receptor	PTAFR	P25105
69	BCL2 related protein A1	BCL2A1	Q16548
70	Pyruvate dehydrogenase kinase 1	PDK1	O15530
71	Spleen associated tyrosine kinase	SYK	P43405
72	Presenilin-1	PSEN1	P49768
73	UDP-glucose ceramide glucosyltransferase	UGCG	Q16739
74	ATPase Na + /K + transporting subunit alpha 1	ATP1A1	P05023
75	Protein geranylgeranyltransferase type I subunit beta	PGGT1B	P53609
76	Galectin 8	LGALS8	O00214
77	Nuclear receptor subfamily 4 group A member 2	NR4A2	P43354
78	Hydroxysteroid 11-beta dehydrogenase 2	HSD11B2	P80365
79	Prostaglandin F receptor	PTGFR	P43088
80	Galectin 4	LGALS4	P56470

GO Enrichment of Putative Targets

Eighty screened ginsenoside Rh2-glioma crossed genes (Table 1) were subjected to the DAVID database, and the functions of the putative targets were further analyzed. With the limit of P value < .05, the putative genes were enriched in indicated processes, of which the top 20 are listed in Figure 2A. In detail, the genes involved in biological process were functions in negative regulation of apoptotic process, cell proliferation, growth hormone receptor signaling pathway, positive regulation of transcription form, RNA polymerase II promoter, and so on (Figure 2B), whereas the putative targets involved in cellular component (CC) participated in regulating centrosome, membrane, spindle microtubule, cytoplasm, nucleus, midbody, and cytosol (Figure 2C). Moreover, the overlapping genes involved in molecular function (MF) were associated with ATP binding, non-membrane spanning protein tyrosine kinase activity, and heme binding (Figure 2D).

Figure 2.

Gene ontology (GO) enrichment of putative targets. GO analysis of the identified targets of the top 20 enrichment (A), and in terms of biological process (B), cellular component (C), as well as molecular function (D).

KEGG Pathway Enrichment Analysis

KEGG pathway analysis revealed that the overlapping targets mediated signaling pathways; the details including the involved genes and indicated signaling pathways are listed in Table 2. Figure 3A shows the top 20 pathways, including cell cycle, cancer, PI3K-Akt, HIS-1, FoxO, and Jak-STAT signaling pathways, in which the bubbles are related with gene number (size) and P value (color) (Figure 3A, Table 2). Furthermore, targets such as EFGR, HDAC2, heat shock protein 90 alpha family class A member 1 (HSP90AA1), vascular endothelial growth factor (VEGFA), B-cell lymphoma-2 like 1 (BCL2L1), and PIK3R1 enriched in cancer pathway are shown in Figure 3B, marked with red stars, tightly related with tumorigenesis and cancer proliferation.

Figure 3.

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. (A) KEGG pathways of the identified targets. (B) Rh2 potential targets enriched in cancer pathway.

Table 2.

Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Enrichment Analysis.

Pathway	Count	P-value	Gene
PI3K-Akt signaling pathway	27	2.13E-17	CSF1R, ITGB3, PIK3CD, PIK3CB, PIK3R1, FGF1, FGF2, EGFR, PIK3CG, ERBB2, KDR, ITGAV, JAK2, PDGFRB, NTRK1, PDGFRA, MAP2K1, HSP90AA1, SYK, IL2, VEGFA, CDK6, PIK3CA, CDK4, KIT, CDK2, BCL2L1
Pathways in cancer	31	5.44E-17	CSF1R, HDAC2, HDAC1, PIK3CD, PIK3CB, PIK3R1, FGF1, FGF2, EGFR, MAPK9, MAPK8, ERBB2, ABL1, ITGAV, JAK2, PDGFRB, NTRK1, PDGFRA, MAP2K1, HSP90AA1, MMP1, MMP2, STAT3, IL2, VEGFA, CDK6, PIK3CA, CDK4, KIT, CDK2, BCL2L1
EGFR tyrosine kinase inhibitor resistance	16	2.21E-16	PDGFRB, PDGFRA, MAP2K1, SRC, STAT3, PIK3CD, PIK3CB, PIK3R1, FGF2, EGFR, VEGFA, PIK3CA, ERBB2, KDR, JAK2, BCL2L1
Pancreatic cancer	14	1.12E-13	MAP2K1, STAT3, PIK3CD, PIK3CB, PIK3R1, EGFR, VEGFA, MAPK9, MAPK8, CDK6, PIK3CA, CDK4, ERBB2, BCL2L1
Proteoglycans in cancer	19	2.12E-13	MAP2K1, SRC, ITGB3, MMP2, STAT3, PIK3CD, PIK3CB, PIK3R1, MAPK14, FGF2, EGFR, MAPK12, VEGFA, PIK3CA, CTSL, ERBB2, KDR, ITGAV, HPSE
Kaposi sarcoma-associated herpesvirus infection	18	1.13E-12	MAP2K1, SYK, SRC, STAT3, PIK3CD, PIK3CB, PIK3R1, MAPK14, FGF2, PIK3CG, MAPK12, VEGFA, MAPK9, MAPK8, CDK6, PIK3CA, CDK4, JAK2
Fluid shear stress and atherosclerosis	16	1.35E-12	HSP90AA1, SRC, ITGB3, MMP2, PIK3CD, PIK3CB, PIK3R1, MAPK14, MAPK12, VEGFA, MAPK9, MAPK8, PIK3CA, CTSL, KDR, ITGAV
Ras signaling pathway	19	1.79E-12	PDGFRB, NTRK1, PDGFRA, CSF1R, MAP2K1, PIK3CD, PIK3CB, PIK3R1, FGF1, FGF2, EGFR, VEGFA, MAPK9, MAPK8, PIK3CA, KIT, KDR, ABL1, BCL2L1
Viral carcinogenesis	18	2.56E-12	HDAC5, HDAC2, HDAC3, SYK, HDAC1, SRC, STAT3, PIK3CD, PIK3CB, PIK3R1, HDAC6, HDAC7, CDK6, PIK3CA, CDK4, CHEK1, CDK2, CDK1
Endocrine resistance	14	3.38E-12	MAP2K1, SRC, MMP2, PIK3CD, PIK3CB, PIK3R1, MAPK14, EGFR, MAPK12, MAPK9, MAPK8, PIK3CA, CDK4, ERBB2
Rap1 signaling pathway	18	4.11E-12	PDGFRB, PDGFRA, CSF1R, MAP2K1, SRC, ITGB3, PIK3CD, PIK3CB, PIK3R1, FGF1, MAPK14, FGF2, EGFR, MAPK12, VEGFA, PIK3CA, KIT, KDR
Progesterone-mediated oocyte maturation	14	5.71E-12	MAP2K1, HSP90AA1, PLK1, PIK3CD, PIK3CB, PIK3R1, MAPK14, MAPK12, AURKA, MAPK9, MAPK8, PIK3CA, CDK2, CDK1
Relaxin signaling pathway	15	7.61E-12	MAP2K1, MMP1, SRC, MMP2, PIK3CD, PIK3CB, PIK3R1, MAPK14, EGFR, MAPK12, VEGFA, MAPK9, MAPK8, MMP13, PIK3CA
Central carbon metabolism in cancer	12	2.66E-11	NTRK1, PDGFRB, PDGFRA, MAP2K1, PIK3CA, ERBB2, KIT, PIK3CD, PIK3CB, PIK3R1, EGFR, PDK1
Prolactin signaling pathway	12	2.66E-11	MAPK9, MAP2K1, MAPK8, PIK3CA, SRC, STAT3, PIK3CD, PIK3CB, PIK3R1, JAK2, MAPK14, MAPK12
Melanoma	12	3.67E-11	PDGFRB, PDGFRA, MAP2K1, CDK6, PIK3CA, CDK4, PIK3CD, PIK3CB, PIK3R1, FGF1, FGF2, EGFR
AGE-RAGE signaling pathway in diabetic complications	13	8.29E-11	MMP2, STAT3, PIK3CD, PIK3CB, PIK3R1, MAPK14, MAPK12, VEGFA, MAPK9, MAPK8, PIK3CA, CDK4, JAK2
Neutrophil extracellular trap formation	16	1.28E-10	HDAC5, MAP2K1, HDAC2, HDAC3, SYK, HDAC1, SRC, ITGB3, PIK3CD, PIK3CB, PIK3R1, MAPK14, MAPK12, HDAC6, HDAC7, PIK3CA
FoxO signaling pathway	14	1.44E-10	MAP2K1, PLK1, STAT3, PIK3CD, PIK3CB, PIK3R1, MAPK14, EGFR, MAPK12, MAPK9, MAPK8, PIK3CA, CDK2, S1PR1
Focal adhesion	16	2.83E-10	PDGFRB, PDGFRA, MAP2K1, SRC, ITGB3, PIK3CD, PIK3CB, PIK3R1, EGFR, VEGFA, MAPK9, MAPK8, PIK3CA, ERBB2, KDR, ITGAV

Conclusion

The current study screens the potential targets of ginsenoside Rh2 in glioma treatment, which are involved in cancer-related signaling pathways, thereby functioning in regulating cell process including cell apoptosis, proliferation, and gene transcription. The results demonstrate the potential mechanisms of ginsenoside Rh2 in glioma treatment.

Discussion

Although ginsenoside Rh2 has been reported as a therapeutic effect on various tumors, including glioma,⁹ the mechanisms of ginsenoside Rh2 in glioma therapy have not been precisely clarified.

In this study, the targets of ginsenoside Rh2 in glioma treatment have been screened. For instance, cell cycle-related protein CDKs, including CDK1, CDK2, CDK4, and CDK6, are identified in the putative targets, suggesting the role of ginsenoside Rh2 in regulating glioma cell cycle as well as cell division. It is reported that ginsenoside Rh2 suppresses various types of human cancer cells’ proliferation and viability, including hepatocellular carcinoma cell lines, leukemia cell lines, colorectal cancer cell lines, breast cancer cell lines, and glioma cell lines.¹⁰ Correspondingly, ginsenoside Rh2 drives glioma cell cycle arrest at G1 phase.⁸ Consistent with this, ginsenoside Rh2 is associated with cell proliferation in the result of GO enrichment (Figure 2A).

Several studies confirmed that histone acetylation exhibits reduced modification level in various types of cancer and correlated with the pathological stages and prognosis.¹¹ In glioma, HDAC class I (HDAC1, 2, 3, 8) as well as HDAC6 are upregulated and corelated with more aggressive phonotype.¹² HDAC inhibitors (HDACi) targeting HDACs have been investigated in cancer therapy; more than 30 inhibitors have been applied in clinic trials, while five HDACis have been approved in clinical cancer treatment.¹³ Our data demonstrated that ginsenoside Rh2 can regulate HDACs’ (HDAC1, 2, 3, 5, 6, 7) expression (Table 1) and functions in regulating histone deacetylase complex and histone deacetylase activity in CC and MF of GO analysis (Figure 2C and 2D), suggesting an HDACs inhibitor role of ginsenoside Rh2 in anti-glioma.

EGFR, a type of receptor tyrosine kinases, is involved in activating several downstream signaling pathways such as PI3K-AKT pathway.¹⁴ EGFR is often overexpressed in various cancer cells, including glioma, and related with cancer cell proliferation, autophagy, and migration.¹⁵ It is reported that ginsenoside Rh2 downregulates the expression level of EGFR and inhibits the proliferation of glioma.⁶ In our result, EGFR is one of the overlapping genes of ginsenoside Rh2 and glioma, through targeting EGFR, ginsenoside Rh2 mediating PI3K-AKT signaling pathway, estrogen signaling pathway, Ras signaling pathway, and FOXO signaling pathway, indicating that ginsenoside Rh2 can target EGFR, function in regulating indicated signal transduction, thereby suppressing glioma progression.

VEGF-mediated angiogenesis plays a critical role in tumor growth, metastasis, and recurrence.¹⁶ Several drugs targeting VEGF and VEGF signaling pathway have been approved by U.S. FDA in various types of cancer, including glioma.^17,18 Study has shown that ginsenoside Rh2 inhibits the expression of VEGFA, thereby suppressing the proliferation of the cells causing oral squamous cell carcinoma.¹⁹ Consistent with this, through the network pharmacology, VEGFA was screened, and further biological analysis revealed that ginsenoside Rh2 regulating VEGF signaling pathway, HIF signaling pathway, Ras signaling pathway, etc. is mediated by VEGFA. In summary, this study reveals ginsenoside Rh2 can inhibit the proliferation and metastasis of glioma by regulating multi-targets and related signaling network.

Footnotes

Acknowledgments

We would like to thank Editage () for English language editing.

Author Contributions

D.H. and X.W. designed the experiments; X.W. and X.Q. performed the experiments; D.H. and X.W. contributed to manuscript preparation.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Xue Wu

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