Abstract
Aims: The biological functions of cyclin B1 (CCNB1) in colon adenocarcinoma (COAD) will be explored in this study. Furthermore, the therapeutic effects and potential molecular mechanisms of ursolic acid (UA) in COAD cells will also be investigated in vitro. Methods: COAD data were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Differentially expressed genes (DEGs) were determined with differential analysis. The biological functions of CCNB1 were analyzed through the GeneCards, the Search Tool for the Retrieval of Interacting Genes (STRING), and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) databases. Therapeutic effects of UA on COAD cell lines HCT-116 and SW-480 were analyzed by CCK-8 and high-content screening (HCS) imaging assay. Flow cytometry was utilized to detect cell cycle changes of SW-480 and HCT-116 cells. Levels of mRNA and expression proteins of HCT-116, SW-480, and normal colon epithelial cells NCM-460 were determined by qRT-PCR and western blot. Results: CCNB1 was highly expressed and acted as an oncogene in COAD patients. CCNB1 and its interacting genes were significantly enriched in the cell cycle pathway. UA effectively inhibited the proliferation and injured COAD cells. In addition, UA arrested cell cycle of COAD cells in S phase. With regard to the molecular mechanisms of UA, we demonstrated that UA can significantly downregulate CCNB1 and its interacting genes and proteins, including CDK1, CDC20, CCND1, and CCNA2, which contributed to cell cycle blocking and COAD treatment. Conclusion: Results from this study revealed that UA possesses therapeutic effects on COAD. The anti-COAD activities of UA are tightly related to suppression of CCNB1 and its interacting targets, which is crucial in abnormal cell cycle process.
Highlights
Colon adenocarcinoma (COAD) is the most commonly diagnosed malignancies among many cancers and a major causing cancerous death throughout the world
It has been reported that inhibition of COAD was associated with reduction of the cell cycle regulator protein Cyclin B1 (CCNB1), which is achieved by upregulating the expression of P21 (Suboj et al, 2012)
Cell transition from G2 phase to M phase is the normal operation of CCNB1, but overexpression of CCNB1 can lead to uncontrolled cell growth and carcinogenesis by binding to its partner CDKs (Wang et al, 2014; Xie et al, 2019)
Summary
Colon adenocarcinoma (COAD) is the most commonly diagnosed malignancies among many cancers and a major causing cancerous death throughout the world. A mushrooming number of research studies demonstrated that cyclin family members conduct a key role in regulating cell cycle progression, and aberrant expression of cyclin would hinder proliferation of tumor cell (Wang et al, 2014; Liu et al, 2015; Xie et al, 2019). CCNB1/CDK1 in mitochondria phosphorylated the complex I (CI) subunits and enhanced CI enzymatic activity, subsequently, mitochondrial respiration is increased, and oxygen consumption and ATP generation are increased, providing efficient biological energy for cells, promoting G2/ M transformation, and shortening the whole progression of cell cycle (Wang et al, 2014; Xie et al, 2019). It has been reported that inhibition of COAD was associated with reduction of the cell cycle regulator protein CCNB1, which is achieved by upregulating the expression of P21 (Suboj et al, 2012)
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