Potential mechanism of Camellia luteoflora against colon adenocarcinoma: An integration of network pharmacology and molecular docking

Abstract

Background: Camellia luteoflora is a unique variety of Camellia in China which is only distributes in Chishui City, Guizhou Province and Luzhou City, Sichuan Province. Its dried leaves are used by local residents as tea to drink with light yellow and special aroma for health care. It has high potential economic medicinal value. Colon adenocarcinoma (COAD) is the third most frequent malignancy and its incidence and mortality is increasing. However, the current common treatments for COAD bring great side effects. In recent years, natural products and their various derivatives have shown significant potential to supplement conventional therapies and to reduce associated toxicity while improving efficacy. In order to overcome the limitations of traditional treatment methods, the global demand and development of natural anti-COAD drugs were increasingly hindered.

Aim: To investigate the potential targets and mechanisms of Camellia luteoflora anti-COAD.

Methods: Nuclear magnetic resonance and mass spectrometry was used to identified the compounds of Camellia luteoflora. Network pharmacology analysis and survival analysis was used in this study to investigate the anti-COAD effect and mechanism of Camellia luteoflora.

Results: Firstly, a total of 13 compounds were identified. Secondly, 10 active ingredients for 204 potential targets were screened and protein-protein interaction analysis showed that TP53, STAT3, ESR1, MAPK8, AKR1C3, RELA, CYP19A1, CYP1A1, JUN and CYP17A1 were hub targets. GO and KEGG enrichment analyses revealed that Camellia luteoflora exerted anti-COAD effect through multiple functions and pathways. Then, the analysis of survival and stage indicated that TP53 was highly expressed in COAD and the overall survival of high-TP53 and high-CYP19A1 COAD patients was significantly shorter than the low group and there was significant difference in MAPK and RELA expression between different stages. Finally, the molecular docking results demonstrated the binding affinities and sites between active ingredients and TP53, STAT3, ESR1.

Conclusion: Our study systematically demonstrated the potential anti-COAD mechanism of Camellia luteoflora and provided a theoretical basis for its further application in the COAD treatment.

Keywords: Camellia luteoflora; Colon adenocarcinoma; Molecular docking; Natural product; Network pharmacology; Tea.

Figure 1

Network pharmacology regulatory mechanisms of Camellia luteoflora in anti-colon adenocarcinoma. COAD: Colon adenocarcinoma; PPI: Protein-protein interaction.

Figure 2

Camellia luteoflora-colon adenocarcinoma potential targets and protein-protein interaction network. A: The 209 potential targets of Camellia luteoflora active ingredients; B: Venn diagram of potential targets prediction; C: The original protein-protein interaction (PPI) network of the interaction targets output by STRING; D: The visualized PPI network of the interaction targets output by Cytoscape; E: The relationship of the top 10 hub genes. COAD: Colon adenocarcinoma.

Figure 3

The expression of hub genes in colon adenocarcinoma patients. Gene expression data from 275 colon adenocarcinoma (COAD) and 349 normal colon cases in the TCGA and GTXx database was used to relationship between the gene expression and the patients prognosis. Compared with the normal groups, the expression of TP53 was significantly increased in the COAD tissues (^aP < 0.05) but there were no statistically significant differences in the expressions of STAT3, ESR1, MAPK8, AKR1C3, RELA, CYP19A1 and JUN in the COAD tissues (P > 0.05).

Figure 4

The relationship of the hub genes with the prognosis of colon adenocarcinoma patients. Kaplan-Meier survival curves were plotted to evaluate the relationship of the hub genes with the prognosis of colon adenocarcinoma (COAD) patients. The blue line represented the low-expression group, and the red line represented the high-expression group. In COAD patients with high expression of CYP19A1 and TP53, the overall survival was shorter than that in the lower expression patients which was statistically significant [p(HR) < 0.05].

Figure 5

The relationship of the hub genes with the stage of colon adenocarcinoma patients. Violin diagrams were used to represent the relationship of the hub genes with the stage of colon adenocarcinoma patients. Pr (> F) value < 0.05 was considered statistically significant which was red in the figure.

Figure 6

Go function and KEGG pathway enrichment analyses. A: Bubble plot of GO function enrichment analysis of the key targets; B: Bar plot of GO function enrichment analysis of the key targets; C: Bubble plot of KEGG pathway enrichment analysis of the key targets; D: Sankey diagram of KEGG pathway enrichment analysis of the key targets. BP: Biological process; CC: Cellular component; MF: Molecular function.

Figure 7

Molecular docking analysis of ten active ingredients with TP53, STAT3 and ESR1. A: Heap map of binding ability between the ten active ingredients and three target proteins (kcal/mol); B: Interaction diagram between ESR1 and chlorogenic; C: Interaction diagram between ESR1 and isoquercitrin; D: Interaction diagram between STAT3 and daucosterol; E: Interaction diagram between STAT3 and isovitexin-2-O-rhamnoside; F: Interaction diagram between TP53 and isovitexin-2-O-rhamnoside; G: Interaction diagram between TP53 and vitrxin-2-O-rhamnoside.