The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells
Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process...
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| Format: | Article |
| Language: | English |
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MDPI AG
2015-09-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/7/3/0867 |
| _version_ | 1797707432436170752 |
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| author | David Qualtrough Phil Rees Beverley Speight Ann C. Williams Christos Paraskeva |
| author_facet | David Qualtrough Phil Rees Beverley Speight Ann C. Williams Christos Paraskeva |
| author_sort | David Qualtrough |
| collection | DOAJ |
| description | Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer. |
| first_indexed | 2024-03-12T06:06:20Z |
| format | Article |
| id | doaj.art-02c9ee4e8d6342b3b3d9f523df547a10 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:06:20Z |
| publishDate | 2015-09-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-02c9ee4e8d6342b3b3d9f523df547a102023-09-03T03:32:44ZengMDPI AGCancers2072-66942015-09-01731885189910.3390/cancers7030867cancers7030867The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer CellsDavid Qualtrough0Phil Rees1Beverley Speight2Ann C. Williams3Christos Paraskeva4Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Faculty of Health and Applied Sciences, University of the West of England, Frenchay, Bristol BS16 1QY, UKSchool of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UKSchool of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UKSchool of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UKSchool of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UKColorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer.http://www.mdpi.com/2072-6694/7/3/0867colorectal cancerWnt signallinghedgehog signallingE-cadherincyclopamineβ-catenin/TcfEMTinvasion |
| spellingShingle | David Qualtrough Phil Rees Beverley Speight Ann C. Williams Christos Paraskeva The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells Cancers colorectal cancer Wnt signalling hedgehog signalling E-cadherin cyclopamine β-catenin/Tcf EMT invasion |
| title | The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells |
| title_full | The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells |
| title_fullStr | The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells |
| title_full_unstemmed | The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells |
| title_short | The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells |
| title_sort | hedgehog inhibitor cyclopamine reduces β catenin tcf transcriptional activity induces e cadherin expression and reduces invasion in colorectal cancer cells |
| topic | colorectal cancer Wnt signalling hedgehog signalling E-cadherin cyclopamine β-catenin/Tcf EMT invasion |
| url | http://www.mdpi.com/2072-6694/7/3/0867 |
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