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Published on: June 17, 2014
Salinomycin exerts anti-colorectal cancer activity by targeting the β-catenin/T-cell factor complex
Zhongyuan Wang1, Liang Zhou1, Yanpeng Xiong1
1Guangdong Key Laboratory for Genome Stability & Disease Prevention, Carson International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China.
Background And Purpose:
Salinomycin is a well-known inhibitor of human cancer stem cells (CSCs). However, the molecular mechanism(s) by which salinomycin targets colorectal CSCs is poorly understood. Here, we have investigated underlying antitumour mechanisms of salinomycin in colorectal cancer cells and three tumour models.
Experimental Approach:
The inhibitory effect of salinomycin on the Wnt/β-catenin pathway was analysed with the SuperTopFlash reporter system. The mRNA expression of Wnt target genes was evaluated with real-time PCR. Effects of salinomycin on β-catenin/TCF4E interaction were examined using co-immunoprecipitation and an in vitro GST pull-down assay. Cell proliferation was determined by BrdU incorporation and soft agar colony formation assay. The stemness of the cells was assessed by sphere formation assay. Antitumour effects of salinomycin on colorectal cancers was evaluated with colorectal CSC xenografts, APCmin/+ transgenic mice, and patient-derived colorectal tumour xenografts.
Key Results:
Salinomycin blocked β-catenin/TCF4E complex formation in colorectal cancer cells and in an in vitro GST pull-down assay, thus decreasing expression of Wnt target genes. Salinomycin also suppressed the transcriptional activity mediated by β-catenin/LEF1 or β-catenin/TCF4E complex and exhibited an inhibitory effect on the sphere formation, proliferation, and anchorage-independent growth of colorectal cancer cells. In colorectal tumour xenografts and APCmin/+ transgenic mice, administration of salinomycin significantly reduced tumour growth and the expression of CSC-related Wnt target genes including LGR5.
Conclusions And Implications:
Our study suggested that salinomycin could suppress the growth of colorectal cancer by disrupting the β-catenin/TCF complex and thus may be a promising agent for colorectal cancer treatment.
Insights
Salinomycin inhibits colorectal cancer growth by blocking the Wnt/β-catenin pathway. This disrupts cancer stem cell (CSC) proliferation and may offer a new treatment strategy for colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Salinomycin is known to inhibit cancer stem cells (CSCs).
- The precise mechanisms by which salinomycin affects colorectal CSCs remain unclear.
- Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the antitumour mechanisms of salinomycin in colorectal cancer.
- To elucidate how salinomycin targets colorectal CSCs.
- To evaluate salinomycin's efficacy in preclinical colorectal cancer models.
Main Methods:
- Analysis of Wnt/β-catenin pathway activity using reporter assays and real-time PCR.
- Assessment of β-catenin/TCF4E complex formation via co-immunoprecipitation and GST pull-down assays.
- Evaluation of cell proliferation, stemness, and antitumour effects in vitro and in vivo models, including xenografts and transgenic mice.
Main Results:
- Salinomycin inhibited β-catenin/TCF4E complex formation, reducing Wnt target gene expression.
- Suppression of transcriptional activity mediated by β-catenin/LEF1 or β-catenin/TCF4E complexes was observed.
- Salinomycin demonstrated significant inhibitory effects on colorectal cancer cell proliferation, sphere formation, anchorage-independent growth, and tumour growth in vivo, including reduced expression of LGR5.
Conclusions:
- Salinomycin suppresses colorectal cancer growth by disrupting the β-catenin/TCF complex.
- This mechanism highlights salinomycin's potential as a therapeutic agent for colorectal cancer.
- Further investigation into salinomycin's role in colorectal cancer treatment is warranted.
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