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Schisandrin B exerts anti-colorectal cancer effect through CXCL2/ERK/DUSP11 signaling pathway

Cancer Cell International volume 25, Article number: 97 (2025) Cite this article

Abstract

Background

Schisandrin B (Sch B) is an active component in Schisandra chinensis exerting anti-cancer effect, but the mechanism is obscure. This study was designed to explore the mechanism of Sch B against colorectal cancer (CRC).

Method

Apparent experiments including cell proliferation, transwell, colony formation, etc. were carried out to assess the anti-cancer effect of Sch B to CRC cell lines, and the RNA-seq was performed prior to bioinformatics analysis to explore the key transcriptome alterations, furthermore, an untargeted metabolomics was carried out to profile the metabolic alterations after the treatment with Sch B and an integrated analysis and experiment validation were completed based on RNA-seq and metabolomics to find the critical mechanism.

Result

The Sch B showed obviously inhibitory effect to cell proliferation, invasion and migration of CRC cell lines with a IC50 value at 75 µM. The RNA-seq and bioinformatics analysis found the ERK/MAPK pathway has been significantly suppressed by the Sch B treatment, while the chemokine, CXCL2, could activate the ERK pathway when binding to its receptor CXCR2. The metabolomics revealed the metabolic profile of CRC cell was remarkably influenced by the Sch B, focusing on the arginine and proline metabolism, ubiquinone, etc. Importantly, the integrated analysis found the DUSP11 connected the ERK pathway and the metabolisms, may mediate the anti-cancer effect of Sch B.

Conclusion

Sch B showed obviously anti-cancer effect to the CRC through inhibiting CXCL2/ERK/DUSP11 axis, but more experiments are needed to figure out the target of Sch B and validate this mechanism in vivo.

Introduction

According to data from the International Agency for Research on Cancer, the number of new colorectal cancer (CRC) cases globally will reach 1.93 million in 2022, accounting for 9.6% of all cancer diagnoses, and the mortality rate will be 9.3%, making it the second leading cause of cancer-related deaths [1]. The incidence rate of CRC continues to show an upward trend in recent years, which brings heavy burden on global health [2]. Almost half of CRC new cases and the majority of cancer deaths came from Asia, especially from China [3]. Although progress has been made in the diagnosis and treatment of CRC, more than 25% of patients still presented with advanced CRC at the time of diagnosis [4, 5]. Except for the surgery, drug therapy is still the backstone for CRC treatment, which mainly includes 5-fluorouracil (5-FU), regorafenib, capecitabine, oxaliplatin, irinotecan and so on; however, these drugs are associated with various adverse reactions that may discontinue the treatment. In addition, the effectiveness of 5-FU in advanced CRC is less than 15%, companying by liver, kidney and marrow adverse reactions. Moreover, long-term administration of 5-FU may result in drug resistance. Hence, the development of new therapeutic drugs for CRC is of great importance.

Schisandrin B(Sch B) is one of the main active components of Schisandra chinensis [6], and significant anti-cancer activity of Sch B in various cancers has been reported, including liver cancer, breast cancer, and lung cancer through multiple mechanisms [7, 8], for example, in liver cancer, Sch B could induce apoptosis and inhibit cancer growth in mice by upregulating Caspase-3 and Bcl-2 family members; and in breast cancer, Sch B could suppress metastasis by modulating epithelial-mesenchymal transition (EMT) and the STAT3 pathway; furthermore, some other studies have reported that Sch B regulated the MAPK, Wnt/β-catenin, and NF-κB signaling pathways to exert its anti-cancer effects. In CRC, a study has demonstrated the anti-cancer activity of Sch B by inducing apoptosis and cell cycle arrest; other studies also proved that Sch B could mitigate CRC progression through inhibiting the production of inflammatory factors IL-1β, IL-6, and TNF-α [9, 10]. However, these mechanisms of Sch B in anti-CRC treatment remain to be elucidated.

In this study, we first assessed the anti-CRC effect of Sch B in different type of CRC cell lines based on apparent experiments, and then performed transcriptomics and bioinformatics analysis to find the potential mechanisms of Sch B in the treatment of CRC; thirdly, the multi-omics analysis comprising of transcriptomics and metabolomics was carried out using Cytoscape to unveil the key pathways, this key pathway was finally validated in in vitro experiments. These results may promote the application of Sch B in the treatment of CRC.

Materials and methods

Reagents

Standard of Sch B(purity > 97%) was provided by MUST Bio-technology Co. Ltd (Chengdu, China). The Enzyme-linked immunosorbent assay (ELISA) kits were from Xinyu Biological CO. Ltd (Shanghai, China). Cell Counting Kit-8 (CCK-8), SDS-PAGE gel and RIPA Lysis buffer were obtained from Beyotime (Shanghai, China). Fetal bovine serum (FBS) was purchased from Gibco (Waltham, CA, USA), and Dulbecco’s Modification of Eagle’s Medium (DMEM) and McCoy’s 5 A Medium were bought from Meilun Biotech (Dalian, China). CXCL2 protein was bought from MEDCHEMEXPRESS LLC (HY-P7190, Shanghai, China). The CellAmp™ Direct RNA Prep Kit, PrimeScript RT Master Mix, and SYBR® Premix Ex Taq™ were obtained from Takara (Beijing, China). Information of primary antibody was provided in Table S1.

Cell culture and proliferation assay

The human CRC cell lines, including HCT-116, HT-29, and SW480, were purchased from Meilun Biotech (Dalian, China), and cultured for cytotoxicity assessments and in vitro experimental validation. The HCT-116 and HT-29 cell lines were cultured in McCoy’s 5 A medium, and the SW-480 cell line was cultured in DMEM medium supplemented with 10% FBS and 1% penicillin-streptomycin; all cell lines were incubated in 10-cm dishes at 37 °C in a humidified atmosphere containing 5% CO2 in the air. All cells were used in experiment or making stock solutions when reaching 80% confluent. Mycoplasma contamination was tested every month.

As reported previously [11], cell viability was assessed under the treatment with different concentrations of Sch B dissolved in 0.1% DMSO. Cells were plated in 96-well plate at a density of 3*103 cells per well for 24 h and then treated with Sch B for 24 h. Subsequently, each well was added with 10 µl CCK-8 reagent and incubated for 2 h to detect the live cells. Absorbance was measured at 450 nm using a multi-mode enzyme marker(Tecan, Research Triangle Park, USA).

For plate colony formation assay, 200 HCT-116 cells were plated into 6-well plates. After culturing with different concentrations of Sch B or 200 ng CXCL2 or their combinations for 2 weeks, the cells were fixed with 4% paraformaldehyde for 30 min and stained with crystal violet. Colony counting was performed using Image J(version 1.8.0) software.

Transwell experiment

The HCT-116 cells suspension containing 5*104 cells/well were inoculated in 24-well transwell chambers with matrigel matrix glue, and the upper chamber was added with the serum-free medium containing Sch B or 200ng/mL CXCL2 or their combination (matrix glue: serum-free medium = 1:4), and the full medium was loaded into the lower chamber(different full medium were prepared ). After incubating for 24 h, the cells were taken out and fixed with 4% paraformaldehyde for 10 min and stained with 0.5% crystal violet dye for 1 min. The remaining cells in the upper chamber were wiped off, and images were observed by microscope.

ELISA assay

HCT-116 cells were cultured in complete medium and divided into control and Sch B groups, and cell culture medium was collected for CXCL1, 2, and 3 levels analysis using ELISA kits after Sch B treatment at 75 µM. ELISA assay was performed following the manufacturers’ instructions. Absorbance was measured at 450 nm using a multi-mode enzyme marker.

RNA-seq and WGCNA analysis

The cell samples in two groups(control and 75 µM Sch B treatment group) were collected for RNA-seq (n = 3 for each group). These cell samples were processed using CloudSeq mRNA enrichment kit and Illumina HiSeq sequencing (Thermo Fisher Scientific, MA, USA) by Shanghai OE Biotech Co., Ltd. (Shanghai, China). Differentially expressed genes (DEGs) between the groups were identified using the Limma Package. The thresholds of the DEGs were set as fold-change (FC) log|FC| ≥ 1.5 and P ≤ 0.05 with fragments per kilobase million (FPKM) value ≥ 0.1.

In this study, the WGCNA analysis was employed to screen the core modules and key targets. The top 50% DEGs with the most significant differential folds were grouped into subgroups based on their different expression patterns to find the core modules, and the genes in core modules that from CRC cells treated with Sch B were collected, and their correlation with CRC was analyzed [12]. Then, the protein-protein interaction (PPI) network of DEGs was constructed by STRING and GeneMANIA databases, and the parameters of the PPI network, such as degree and topological coefficient, were calculated to carry out the key targets using Cytoscape software. All results were visualized using the ggplot2 package.

GO and KEGG enrichment analysis

The GO and KEGG databases are critical tools in biological research. Researchers can roughly understand the biological functions and dig out signaling pathways by combining GO and KEGG enrichment analysis [13]. To further confirm DEGs functions, the targets of Sch B against CRC were imported into the ClusterProfiler and org.Hs.eg.db packages for GO and KEGG analysis. The GO analysis data, including biological process (BP), cellular component (CC), and molecular function (MF), were obtained and ranked, and KEGG results were also ranked and aggregated by GSEA analysis to find better the pathway information and mechanism of Sch B against CRC. Finally, all enrichment analysis results were ranked, and the terms with the highest scores were displayed by the ggplot2 package.

Expression analysis of CXC-Ligands in CRC

Pan-cancer analysis can rapidly analyze and forecast the expression levels of genes in different cancers based on RNA-seq data provided by public databases, and it is an essential tool for cancer research [14]. The TIMER 2.0 database (http://cistrome.org/TIMER/) collected and normalized pan-cancer data from the TCGA and GTEx databases [15]. The pan-cancer dataset was downloaded from the TIMER 2.0 database. Furthermore, the expression data of seven ligand genes of the core target CXCR2 were extracted in the colon and rectum cancers, including chemokine CXCL1, 2, 3, 5, 6, 7, and 8. Then all samples with expression levels of 0 were filtered, and each sample expression was transformed by log2(x + 0.001). Finally, the expression data of the seven ligands were obtained in the three cancer types. First, the differences of expression levels between normal and cancer samples in colon and rectum cancer were calculated, and significance analysis was performed to screen out the core genes using the unpaired Wilcoxon Rank Sum test and Signed Rank test. In addition, differences in the expression levels of core genes in the three cancers with different clinical stages were also calculated. The independent student-t-test method was used to analyze the difference.

Metabolomics analysis

About 1.2*106 /well of HCT116 cells were treated with Sch B(75 μM) or vehicle for 24 h as the control and experimental groups (n = 3), and the cells were broken using 4 ℃ methanol(maximum 1 mL, a parallel experiment was carried out to measure the cell number to normalize the volume of methanol), and the mixture was harvested and stored at -80℃. The supernatant sample was transferred to metabolomics analysis after being thawed at room temperature and centrifuged at 13,400×g for 10 min. The QC sample was prepared using 10 µL aliquots from every sample. To better elucidate the metabolic alterations of Sch B in anti-CRC treatment, the cellular samples were analyzed using the UPLC/Q-TOF-MS method, and the data analysis, differential ions identification, and enrichment analysis were finished as we reported before [16]. Briefly, the sample determination was completed in a Waters UPLC system (ACQUITY UPLC I-Class) coupled to a quadrupole time-of-flight mass spectrometer (Xevo G2-XS). The ACQUITY UPLC ®HSS T3 column (2.1 × 100 mm, 1.8 μm, Milford, MA, USA). The mobile phase consisted of A: 0.1% formic acid aqueous solution and B: methanol. The collected data were pretreated using Progenesis® QI (Version 2.0), and the multivariate statistical analysis was accomplished using EZinfor 3.0 or SIMCA 14.1 software.

Multi-omics integrated analysis of metabolomics and RNA-seq

To obtain an in-depth and comprehensive understanding of the mechanism of Sch B against CRC, we constructed an integrated network based on metabolomics and RNA-seq. The differential metabolites identified by metabolomics were imported into the Cytoscape software, and key genes and enriched pathway information obtained from RNA-seq, WGCNA, and KEGG enrichment analysis were also imported into the Cytoscape software. Then, the Metscape plug-in program was used to perform integrated analysis of RNA-seq and metabolomic results and to construct the “Compound-Reaction-Enzyme-Gene” network.

Plasmids construction and cell transfection

The DUSP11 knockout plasmid was designed following previous research reports [17], synthesized and packaged into lentivirus by Newhelix Biotech, Co., Ltd (Shanghai, China). The plasmid was transfected using Lipofectamine 3000 reagent for 48 h, followed by the replacement of the fresh complete medium for further experiments.

Western blotting

The HCT-116 cells were divided into different groups, and treated with CXCL2, Sch B or vehicle or other conditions. The HCT-116 cells were rinsed with 1×PBS, and the total protein was extracted using RIPA Lysis buffer mixed with PMSF buffer at 4℃, and the loading buffer was used to prepare the total protein. Then, the total protein concentrations of all groups were normalized by BCA assay kit, and equivalent proteins samples were added to 12% SDS-PAGE gels to electrolyze and isolate at constant voltage (150 V), and then gels were transferred to PVDF membranes and sealed in 5% skim milk powder for 1 h. Next, PVDF membranes were incubated overnight at 4℃ with diluted primary antibody and incubated at room temperature, followed by 2 h with secondary antibody. Lastly, the rinsed PVDF membranes were visualized according to ECL Western Blotting Assay Kit instructions. The protein immunoblot grayscale was measured using ImageJ (version 1.8.0), and GAPDH was used as an internal reference.

Real-time qPCR

Total RNA was isolated and extracted from HCT-116 cells using the RNA extract Kit (Takara, China). The PrimeScript™ RT Master Mix (Takara, Shiga, Japan) was applied to reverse transcribe RNA into cDNA according to instructions, and SYBR® Premix TaqTMII (Takara, Shiga, Japan) was employed for RT-PCR detection (n = 3). Then, all results were quantified using the 2-ΔΔCt method with GAPDH as an internal reference. The specific primers in the procedure were designed and purchased by Sangon Biotech Co., Ltd. (Shanghai, China), and primer sequences are listed in Table S2.

Statistical analysis

The statistical analysis and visualization were performed with GraphPad Prism 9.0, and the results were expressed as mean ± SEM. Student t-test and one-way analysis of variance (ANOVA) were employed to compare groups. P < 0.05 (*), P < 0.01 (**) and P < 0.001 (***) were considered statistically significant.

Results

Sch B inhibited CRC cell proliferation and migration

A series of concentrations (200, 100, 50, 25, 12.5 µM) of Sch B were added to treat HCT-116 cells for 24 h and the results showed that the IC50 for Sch B in inhibiting HCT-116 proliferation was 75 µM (Fig. 1A). Furthermore, Sch B exhibited significant proliferation inhibition in HCT116, HT-29, and SW480 cell lines (Fig. 1B) when treated with 75 µM for 24 h. The colony formation assay with Sch B at 50, 75, 100 µM further confirmed that Sch B inhibited the proliferation of HCT-116 cells, consistent with the abovementioned results (Fig. 1C-D). Additionally, this study evaluated the effect of Sch B on HCT-116 cell apoptosis using the TUNEL assay, and the results proved that treatment with 75 µM Sch B significantly increased apoptosis of HCT-116 cells (Fig. S1A). To assess invasion and migration of CRC cell treated with Sch B (15 and 30 µM), the transwell assay was performed and the results demonstrated that Sch B significantly inhibited the invasion and migration of HCT-116 cells (Fig. 1E-F). Results of the wound healing assay also proved that Sch B(75 µM) could significantly inhibit the migration of HCT116 (Fig. S1B). These apparent studies demonstrated that Sch B remarkably inhibited CRC cell proliferation, migration, and invasion and promoted apoptosis, thereby exerting its anti-CRC effects.

Fig. 1
figure 1

Sch B inhibited the cell proliferation, migration and invasion of CRC cell lines. (A) the IC50 value experiment of HCT116 cell line treated with 200, 100, 50, 25, 12.5 µM Sch B or vehicle for 24 h. (B) the Sch B(75 µM) inhibited the cell proliferation of different CRC cell lines. (C-D) the HCT116 cells were treated with 50, 75, 100 µM Sch B and the colony formation was obviously suppressed. (E-F) the HCT116 cells were treated with 15, 30 µM Sch B and the migration and invasion were both inhibited.

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ERK signaling pathway was downregulated by Sch B identified via RNA-Seq and WGCNA analysis

To further explore the targets and mechanisms of anti-CRC effect of Sch B, RNA-seq was performed for the samples from the control group and Sch B treatment group(75 µM), and the differentially expressed genes (DGEs) between the two groups after treatment for 12 h were identified using the Limma program. Volcano plot analysis showed a significant distinction among two groups, suggesting that the Sch B could affect the gene expression profile of HCT116 cells (Fig. 2A); furthermore, heatmap revealed genes with significant expression level after Sch B treatment, for example, CCN2, ALPK2, THBS2, and SHISA7, etc. (Fig. 2B). The DEGs were further subjected to WGCNA, and module clustering gave a total of 17 modules (Fig. S2A) when the soft threshold was set at 1 (Fig. S2B). Then, the module-group correlation analysis was carried out and the results showed modules with dark turquoise color and dark magenta color were the most core modules (Fig. S2C). The correlation scatter plots presented significant correlations between genes in these two core modules and DEGs (Fig. S2D).

Fig. 2
figure 2

Sch B downregulated the ERK/MAPK signaling pathway by decreasing the phosphorylation level of ERK. (A) Volcano plot showed the DEGs after 75 µM Sch B treatment for 12 h. (B) the heatmap of DEGs versus the group. (C) pathway enrichment analysis of DEGs based on the KEGG database showed the MAPK pathway was significantly influenced by the Sch B treatment. (D) the GSEA analysis confirmed the most influenced pathway by the Sch B treatment. (E-F) the measurement of phosphorylation level of three subpathways of MAPK after the treatment with Sch B

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KEGG pathway enrichment of genes in two core modules demonstrated the top 20 signaling pathways were most associated with Sch B treatment, among which MAPK signaling pathway played a critical role in anti-CRC effect of Sch B (Fig. 2C), besides, the results of GSEA analysis also confirmed the key role of MAPK signaling pathway in this effect of Sch B (Fig. 2D). Next, the GO enrichment analysis was performed and the results showed that the genes in core modules were mainly enriched in tube morphogenesis, vasculature development, and blood vessel development, etc. (Fig. S2E-F). MAPK signaling pathway, which mainly includes P38, ERK, and JNK sub-pathways, has been reported to play essential roles in multiple biological processes, for instance, the proliferation and metastasis in CRC. To determine which sub-pathway has been suppressed after the treatment of Sch B, the phosphorylation levels of them were measured and the results presented significantly lower phosphorylation level of ERK in HCT-116 cells treated with Sch B compared with the control group, while the other two proteins, P38 and JNK, showed no significant changes in their phosphorylation levels (Fig. 2E-F). Collectively, these results suggested that Sch B may exert its anti-CRC effects by inhibiting the ERK/MAPK signaling pathway.

CXCL2 was revealed as key protein promoting CRC proliferation through ERK pathway

The genes in two core modules were imported into the STRING database to obtain the PPI information. The PPI network was constructed through analysis the top 10 targets by employing the GeneMANIA database (Fig. 3A). Then the CXCR2 was found as the core protein in the PPI network using Cytoscape and MCODE plug-in (Fig. 3B). There were seven ligands for the CXCR2 receptor, including CXCL1, 2, 3, 5, 6, 7, and 8. The expression levels of seven ligands in CRC tissue or normal tissue were obtained from TCGA and GTEx databases, and the results indicated that CXCL1, CXCL2, and CXCL3 showed higher expression levels in CRC compared with other four ligands. Further analysis found that compared with the normal tissue, the expression levels of CXCL1, 2 and 3 in tumor group were all significantly elevated in tumor tissue (Fig. 3C-D). Then, we compared the expression levels of CXCL1, 2 and 3 in different stage of CRC, and interestingly, the expression levels of these three ligands negatively correlated to the stage of CRC, and CXCL2 decreased most (Fig. 3E). To confirm the expression levels of CXCL1, 2 and 3, the RT-qPCR assay and ELISA were performed in HCT116 cells treated with Sch B, and the results showed that CXCL2 had the biggest difference among three ligands (Fig. 3F-G). In a word, the CXCL2 was considered as the core target of Sch B in the treatment of CRC.

Fig. 3
figure 3

Bioinformatic analysis revealed the CXCL2 as the key protein promoting CRC proliferation. (A) construction of PPI network through analysis the top 10 targets. (B) the CXCR2 was found to be the core target in the PPI network. (C-D) the CXC-Ligands expression levels was analysis based on TIMER 2.0 database, and the CXCL1, 2 and 3 were proved to the higher expressed ligands in tumor tissues. (E) the correlation of CXCL1, 2 and 3 levels and the cancer T stage. (F-G) the treatment with 75 µM Sch B evidently downregulated the expression levels of CXCL2

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Based on the results of RNA-seq and bioinformatics analysis, we supposed that CXCL2 was an essential protein promoting CRC progression through ERK pathway. To prove the connection between CXCL2 and ERK pathway, a transwell assay was first carried out and the results showed that CXCL2 could promote the migration of HCT-116 cells, while the migration of HCT-116 cells was inhibited after treatment with Sch B (Fig. 4A and C), with similar results observed in cell colony formation (Fig. 4B and D). Importantly, this study further found CXCL2 could significantly increase the phosphorylation level of ERK, but the phosphorylation level of ERK was reversed by adding the Sch B (Fig. 4E-F). These results suggest that Sch B could inhibit the progression of CRC through the CXCL2/ERK pathway.

Fig. 4
figure 4

Validating the critical role of CXCL2 in promoting the cell proliferation, migration and colony formation. (A-D) Sch B inhibited the cell migration and colony formation promoted by the CXCL2. (E-F) the CXCL2-enhanced phosphorylation level of ERK was reversed by the Sch B treatment

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Metabolomics analysis profiled the metabolic alterations of HCT116 treated with Sch B

To analyze the metabolic alterations caused by the Sch B treatment, this study first constructed a principal component analysis (PCA) model to show the comprehensive difference between different groups and the reliability of detection process, and the scatter plot showed an obvious difference between Sch B treatment group and the control group after a reliable detection and analysis process (Fig. 5A in positive ionization mode and Fig S3A in negative ionization mode). Next, an orthogonal partial least squares–discriminant analysis (OPLS-DA) model was developed and the metabolic profile of the Sch B differed significantly from that in control group (Fig. 5B, R2X = 0.86, Q2 = 0.99 in positive ionization mode and Fig S3B, R2X = 0.70, Q2 = 0.40 in negative ionization mode), and 200 times of permutation tests were carried out, which verified the reliability of the OPLS-DA model (Fig. 5C, R2 = 1, Q2 = 0.91 in positive ionization mode and Fig S3C, R2 = 0.59, Q2=-0.3.9 in negative ionization mode). The S-plot and Loading plot were drawn to dissect the metabolic network alteration and find the differential ions (Fig. 5D-E in positive ionization mode and Fig S3D-E in negative ionization mode), 339 differential ions in positive ionization mode and 3 differential ions in negative ionization mode with p-value less than 0.05 and VIP value more than 1 from Sch B group vs. control group comparisons were selected for ion identification in HMDB and METLIN database using the QI software. Finally, 2 metabolites in negative ionization mode and 27 metabolites in positive ionization mode were identified and verified using their standards (Table S3). A pathway enrichment analysis was performed for these differential metabolites, and the results found that these metabolites were most involved in the arginine and proline metabolism, ubiquinone and other terpenoid-quinone biosynthesis, beta-alanine metabolism, etc. (Fig. 5F). Sch B treatment significantly disturbed the metabolic profile of CRC.

Fig. 5
figure 5

Metabolic profile was remarkably disturbed by the treatment with Sch B. (A) the PCA model in positive ionization mode showed the reliability of detection and analysis processes. (B) the OPLS-DA model in positive ionization mode proved the huge difference of metabolic profiles between the control group and Sch B treatment group. (C) a 200 times of permutation test proved the reliability of OPLS-DA model. (D-E) construction of the Volcano plot and S-plot to select the differential ions between groups. (F) the pathway enrichment analysis of the differential compounds

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Integrated analysis and validation of metabolomics and RNA-seq

After importing key genes and differential compounds into the Metscape program, the “compound-response-enzyme-gene” network was constructed through integrated metabolomics and RNA-seq analysis. The results showed that the MAPK signaling pathway, the top1 pathway with the highest correlation in KEGG enrichment analysis, played a center role in the network, and the key genes in the MAPK signaling pathway included MAPK1, 3, 6, 8, 9, 11, 12, 13 and 14. The results of the RT-qPCR assay presented significantly reduced all key genes in HCT-116 cells after Sch B treatment (Fig. S4A). The integrated analysis results also displayed that the MAPK signaling pathway was mainly associated with metabolic pathways such as aminosugar metabolism, glycolysis and gluconeogenesis, pyrimidine metabolism, and others. Most importantly, the DUSP11, a phosphorylase, was found to be the only channel to link the MAPK signaling pathway and downstream metabolism pathways (Fig. 6A). Thus, DUSP11 may mediate the anti-cancer effect of Sch B to CRC through the MAPK signaling pathway. This study further observed that Sch B treatment could significantly upregulate DUSP11 expression in HCT116 cells, and a positive correlation between Sch B concentration and the expression level of DUSP11 was displayed (Fig. 6B-C).

Fig. 6
figure 6

Integrated analysis of transcriptomics and metabolomics revealed the critical role of DUSP11 in the anti-cancer effect of Sch B. (A) the DUSP11 was the only protein connecting the transcriptomics and metabolomics. (B-C) the Sch B inhibited the expression level of DUSP11 in a dose dependent manner. (D-F) ERK negatively regulated the expression level of DUSP11 and DUSP11 could dephosphorylate of ERK

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To further confirm the critical role of DUSP11 in anti-cancer effect of Sch B, we successfully knocked out DUSP11 in HCT-116 cells to verify its role in CXCL2/ ERK pathway (Fig. S4B), and this knockout of DUSP11 decreased the phosphorylation of ERK (Fig. 6D); in addition, the ERK agonist (LM22B-10) or antagonist (PD98059) was applied, and the results showed that treatment with the ERK agonist significantly reduced the expression of DUSP11 but promoted the cell migration, while antagonist upregulated the expression of DUSP11 (Fig. 6D-E) but inhibited the cell colony formation and migration (Fig S4C). These results indicated that the phosphorylation level of ERK could negatively regulate the expression of DUSP11, furthermore, after the knockout of DUSP11, the phosphorylation level of ERK in HCT-116 significantly increased, demonstrating that DUSP11 and p-ERK have critical influence on each other (Fig. 6F). In summary, our results confirmed that Sch B could exert anti-CRC effect through inhibiting CXCL2/ERK/DUSP11 axis.

Discussion

Although chemotherapeutic, immune and targeted agents have significantly mitigated the progression of CRC and improved patients’ prognosis, adverse reactions and resistance have hindered their clinical application in the treatment of CRC [18, 19]. Therefore, developing superior therapeutic agents for treating CRC is urgently needed. Traditional Chinese medicine (TCM) has an irreplaceable position in preventing and treating CRC due to its unique advantages of multi-pathway, multi-target, and low toxicity. Schisandra chinensis Turcz. (Baill.), a traditional Chinese herb widely used in China and many East Asian countries, has significant therapeutic effects on CRC through liver protection, anti-oxidant, and anti-inflammatory, and other pathways [20]. Sch B is the main active ingredient in Schisandra chinensis Turcz. (Baill.) in cancer treatment, and many studies have shown its anti-cancer activity to a variety of cancers, for example, hepatocellular carcinoma, breast cancer, and gastric cancer [21, 22]. Besides, Sch B is an inhibitor of P-glycoprotein and multidrug resistance protein, which may exert synergistic effect with many anti-cancer agents [23, 24]. In CRC, a recent study reported that Sch B inhibited CRC progression by inducing cell cycle arrest and promoting apoptosis [25]; another study stated Sch B could attenuates colitis-associated CRC through SIRT1 linked SMURF2 signaling [10]; we also reported that Sch B could inhibit the CRC cell line HCT116, which may be associated with its higher exposure level in cell nucleus [26]. However, the mechanism of the Sch B anti-CRC remains to be elucidated.

In this study, we combined multi-omics and bioinformatics analysis to identify the key targets and mechanisms of Sch B against CRC, and validated it in in vitro cellular model. RNA-seq, WGCNA, and PPI analysis were employed to find core targets of Sch B therapy for CRC. The results observed that CXCR2 receptor played an important role. CXCR2, also known as IL-8RB, is a typical G-protein-coupled receptor, which exerts its bioactive effects through binding the ligands of the CXC chemokine family, including CXCL1, 2, 3, 5, 6, 7 and 8. Previous studies have proved that a higher level of CXCR2 in cancer cells is associated with poor prognosis in CRC patients, and blocking CXCLs/CXCR2 signaling could inhibit the proliferation and migration of cancer cells and decrease tumor angiogenesis [27, 28]. Many studies reported that the CXCR2 binding to its ligands showed powerful chemotaxis of neutrophils or myeloid-derived suppressor cells (MDSC) and was related to tumor angiogenesis, progression, and chemoresistance [29,30,31]. To further pinpoint the key chemokine ligands of CXCR2, we performed a comprehensive pan-cancer analysis of seven ligands, and then these results of pan-cancer analysis were combined with RT-qPCR assays and finally CXCL2 was identified as the most critical ligand. CXCL2 is a common chemotactic cytokine secreted by various cells, such as monocytes and macrophages [32, 33]; and it has been reported play the critical role in driving cancer progression [34, 35]. Since the expression of CXCL2 is abnormally elevated in CRC tissue, it is considered as a putative prognostic biomarker for CRC [36,37,38]. CXCL2 can stimulate CRC cell lines, leading to cancer proliferation and migration by binding to the CXCR2 receptor [32], and the correlation between CXCL2 and CRC metastasis may be explained by CXCL2-induced cancer stem cell-promoting potential [39]. Therefore, inhibiting CXCL2 secretion or blocking its binding to CXCR2 may suppress CRC progression and metastasis, representing an effective therapeutic strategy for CRC treatment. However, this study just confirmed that Sch B can inhibit the secretion of CXCL2 in CRC cells, but whether the anti-CRC effect of Sch B is related to its binding with CXCR2 and blocking the CXCL2/CXCR2 axis still necessitates further exploration.

Through integrated RNA-seq and metabolomics analysis, this study identified an essential role of DUSP11 between the MAPK signaling pathway and the metabolic pathways. DUSP11 is a dual-specificity protein phosphatase that has been implicated as a significant modulator of dysregulated signaling pathways in various diseases, DUSP11 can dephosphorylate various phosphorylated proteins, such as MAPK pathway related proteins [40, 41]. The gene family that encodes DUSP11 could also express PTENs, MKPs, and others [42]; Some studies showed that MKPs could dephosphorylate MAPK proteins to show anti-cancer effect [27, 43,44,45]. But the roles of DUSP11 in CRC is still obscure. In this study, we demonstrated that Sch B could upregulate DUSP11, inhibit ERK phosphorylation level, and thereby inhibit ERK pathway activation to achieve anti-CRC effect. These results suggest that Sch B can inhibit CRC proliferation and migration through CXCL2/ERK/DUSP11 axis; however, further studies need to be carried out to (1) found the direct target of Sch B regulating the CXCL2/ERK/DUSP11 axis; (2) elucidate how the Sch B regulates the DUSP11, and (3) verify these results in vivo.

Conclusion

This study first reported a novel mechanism of Sch B in the treatment of CRC, and the CXCL2/ERK/DUSP11 axis was identified as the key pathway of Sch B against CRC through integrated multi-omics analysis, bioinformatic analysis and experiment validation. These results may deepen our understanding of anti-cancer effects of traditional medicine and provide evidence to support the clinical treatment of CRC using Sch B.

Data availability

No datasets were generated or analysed during the current study.

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Funding

This study was supported by the National Natural Science Foundation of China (82204819, U23A20512), Shanghai Municipal Health Commission (20214Y0319), and Bethune Charitable Foundation: Shining China - Pharmaceutical Research Capacity Building Funding (Z04JKM2023E040).

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  1. Jianguo Sun, Zhipeng Wang and Yunlei Yun contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, No. 415, Fengyang Road, Shanghai, 200003, P. R. China

    Jianguo Sun, Zhipeng Wang, Yunlei Yun, Zhijun Liu, Lili Cui, Mao Tang, Wansheng Chen & Shouhong Gao

  2. College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, 650500, P. R. China

    Jianguo Sun, Liya Ye, Zhengyan Liang & Shouhong Gao

  3. Guangzhou City Key Laboratory of Subtropical Fruit Tree Outbreak Control, Zhongkai University of Agriculture and Engineering, Guangzhou, 510225, P. R. China

    Yingqi Feng

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Contributions

Shouhong Gao and Wansheng Chen designed and supervised the study. Jianguo Sun, Zhipeng Wang and Yunlei Yun analyzed and interpreted the data, and wrote the original draft. Yingqi Feng, Zhijun Liu, Lili Cui, Mao Tang, Liya Ye and Zhengyan Liang collected the data and visualized the data. All authors contributed to the writing of this manuscript. All authors read and approved the final manuscript.

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Correspondence to Wansheng Chen or Shouhong Gao.

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Sun, J., Wang, Z., Yun, Y. et al. Schisandrin B exerts anti-colorectal cancer effect through CXCL2/ERK/DUSP11 signaling pathway. Cancer Cell Int 25, 97 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03727-9

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Cancer Cell International

ISSN: 1475-2867

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