title: The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells.
abstract: 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.
authors.affiliation: Department 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, UK. david.qualtrough@uwe.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Qualtrough
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK. phil.p.rees@gmail.com.
authors.forename: Phil
authors.initials: P
authors.lastname: Rees
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK. bevspeight@yahoo.com.
authors.forename: Beverley
authors.initials: B
authors.lastname: Speight
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK. ann.c.williams@bristol.ac.uk.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Williams
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK. c.paraskeva@bristol.ac.uk.
authors.forename: Christos
authors.initials: C
authors.lastname: Paraskeva
keywords: E-cadherin; EMT; Wnt signalling; colorectal cancer; cyclopamine; hedgehog signalling; invasion; β-catenin/Tcf