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Nitidine chloride inhibits colorectal cancer by targeting BUB1: mechanistic insights from molecular dynamics
Ke-Jun Wu1, Jin-Cheng Li2, Li-Min Liu3
1Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China.
Background:
Colorectal cancer (CRC) is a prevalent malignancy with the efficacy of current treatments limited. Nitidine chloride (NC), a natural alkaloid, exhibits antitumor potential, but its mechanism in CRC remains unclear.
Objective:
To investigate the antitumor effects and mechanisms of NC in CRC for clinical therapeutic strategies.
Methods:
A Cell Counting Kit-8 was used to assess the viability of HCT116 cells. Xenograft mice received NC (2, 4, 8 mg/kg, intraperitoneal, once every other day for 2 weeks). Transmission electron microscopy and hematoxylin-eosin staining analyzed tumor ultrastructure and pathology. RNA sequencing, real-time quantitative polymerase chain reaction, and molecular dynamics simulation (MDS) examined gene expression and NC-budding uninhibited by benzimidazoles 1 (NC-BUB1) interaction. Single-cell RNA sequencing, spatial transcriptomics, immunohistochemistry, and chromatin immunoprecipitation sequencing explored BUB1 expression and RAD21 regulation. Immune correlation analysis was conducted using TISIDB, TIMER2.0, and deconvolution algorithms (CIBERSORT, CIBERSORT-ABS, EPIC, ESTIMATE, MCPcounter, quanTIseq, TIMER, xCell) to evaluate associations between BUB1 and immune factors or infiltration.
Results:
NC inhibited HCT116 cells with time- and concentration-dependent half-maximal inhibitory concentration reduction. NC-treated tumors displayed apoptosis and reduced angiogenesis. Transcriptomics identified BUB1 as a core downregulated gene. Multi-omics confirmed BUB1 overexpression in CRC (1293 vs. 2299 samples; standardized mean difference = 1.77, area under the curve = 0.94) in proliferative/malignant regions. Immune analyses revealed that high BUB1 expression correlated negatively with antigen presentation molecules, chemokines/receptors, and immune cell infiltration (B cells, M2 macrophages, cancer-associated fibroblasts, endothelial cells), suggesting immune microenvironment suppression. BUB1 knockout inhibited CRC cells; NC reduced BUB1 expression. MDS showed a stable NC-BUB1 complex (- 8.8 kcal/mol). The RAD21-BUB1 axis exerted key regulatory roles.
Conclusion:
NC exerts anti-CRC effects by downregulating BUB1, disrupting the RAD21-BUB1 axis, and alleviating BUB1-mediated immune suppression.
Insights
Nitidine chloride (NC) shows antitumor effects against colorectal cancer (CRC) by downregulating BUB1 expression. This natural alkaloid disrupts the RAD21-BUB1 axis, inhibiting tumor growth and suppressing the immune microenvironment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Colorectal cancer (CRC) presents a significant clinical challenge due to limited treatment efficacy.
- Nitidine chloride (NC), a natural alkaloid, demonstrates potential antitumor activity, but its precise mechanisms in CRC require elucidation.
Purpose of the Study:
- To investigate the antitumor effects and underlying mechanisms of Nitidine chloride (NC) in colorectal cancer (CRC).
- To explore the potential of NC as a therapeutic strategy for CRC treatment.
Main Methods:
- Cell viability assays (Cell Counting Kit-8) and xenograft mouse models were employed to assess NC's efficacy.
- Multi-omics approaches including RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics were used to identify key molecular targets.
- Molecular dynamics simulations and immune correlation analyses were performed to elucidate the interaction between NC, BUB1, RAD21, and the tumor immune microenvironment.
Main Results:
- NC inhibited CRC cell viability and reduced tumor growth, apoptosis, and angiogenesis in vivo.
- Transcriptomic analysis identified BUB1 as a core downregulated gene, with high BUB1 expression linked to CRC malignancy and immune suppression.
- NC was shown to directly interact with BUB1, reducing its expression and disrupting the RAD21-BUB1 axis, thereby alleviating immune evasion.
Conclusions:
- Nitidine chloride (NC) exerts significant anti-CRC effects through the downregulation of BUB1.
- Disruption of the RAD21-BUB1 axis by NC plays a crucial role in its antitumor activity.
- NC demonstrates potential for overcoming BUB1-mediated immune suppression in colorectal cancer, offering a promising therapeutic avenue.
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