Monotropein Induced Apoptosis and Suppressed Cell Cycle Progression in Colorectal Cancer Cells
Quan Gao1,2, Lin Li1,2, Qi-Man Zhang1,2
1School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China.
Objective:
To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer (CRC) through network pharmacology and molecular docking combined with experimental verification.
Methods:
Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway.
Results:
The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase (Akt1, Akt2), cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-9 (MMP9), epidermal growth factor receptor (EGFR), cell division control protein 42 homolog (CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets (Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein (P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G1-S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9 (P<0.05), and might play an anticancer role through Akt signaling pathway.
Conclusion:
Monotropein exerts its antitumor effects primarily by arresting the cell cycle, causing cell apoptosis, and inhibiting cell migration. This indicates a high potential for developing novel medication for treating CRC.
Insights
Monotropein demonstrates anticancer effects against colorectal cancer (CRC) by inducing apoptosis, arresting the cell cycle, and inhibiting cell migration. This natural compound shows promise for novel CRC therapeutic development.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Colorectal cancer (CRC) remains a significant global health challenge.
- Identifying novel therapeutic agents with distinct mechanisms of action is crucial for improving CRC treatment outcomes.
Purpose of the Study:
- To investigate the anticancer potential of monotropein against colorectal cancer (CRC).
- To elucidate the underlying molecular mechanisms of monotropein's anti-CRC activity using network pharmacology, molecular docking, and experimental validation.
Main Methods:
- Network pharmacology and molecular docking were employed to predict monotropein's potential molecular targets in CRC.
- In vitro experiments including cell counting kit assays, flow cytometry, and Western blotting were conducted on CRC cell lines (HCT116, HT29, LoVo).
- Assays assessed antiproliferative effects, apoptosis induction, cell cycle progression, cell migration, and key protein expression, including the Akt pathway.
Main Results:
- Monotropein exhibited significant antiproliferative effects on HCT116, HT29, and LoVo colorectal cancer cells.
- The compound induced apoptosis by modulating Bcl-2 and Bax expression and caused G1-S cell cycle arrest via regulation of CyclinD1, CDK4, and CDK6.
- Monotropein inhibited cell migration by suppressing CDC42 and MMP9 expression, potentially acting through the Akt signaling pathway.
Conclusions:
- Monotropein possesses significant antitumor properties against colorectal cancer.
- Its mechanisms involve cell cycle arrest, apoptosis induction, and inhibition of cell migration, highlighting its potential as a novel therapeutic agent for CRC.
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