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Impact of mutant beta-catenin on ABCB1 expression and therapy response in colon cancer cells

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Item Type:Article
Title:Impact of mutant beta-catenin on ABCB1 expression and therapy response in colon cancer cells
Creators Name:Stein, U. and Fleuter, C. and Siegel, F. and Smith, J. and Kopacek, A. and Scudiero, D.A. and Hite, K.M. and Schlag, P.M. and Shoemaker, R.H. and Walther, W.
Abstract:Background: Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/beta-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function beta-catenin on the chemoresistant phenotype. Methods: The effect of mutant (mut) beta-catenin on ABCB1 expression and promoter activity was examined using HCT116 human colon cancer cells and isogenic sublines harbouring gain-of-function or wild-type beta-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening. Results: Cell lines with mut beta-catenin showed high ABCB1 promoter activity and expression. Transfection and siRNA studies demonstrated a dominant role for the mutant allele in activating ABCB1 expression. Patients' primary colon cancer tumours shown to express the same mut beta-catenin allele also expressed high ABCB1 levels. However, cell line chemosensitivities towards 24 MDR-related and non-related antitumour drugs did not differ despite different beta-catenin genotypes. Conclusion: Although ABCB1 is dominantly regulated by mut beta-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same beta-catenin mutation was detected. The functional significance of the mutation for predicting patients' therapy response or for individualisation of chemotherapy regimens remains to be established.
Keywords:Colon Cancer, Beta-Catenin, Multidrug Resistance, ABCB1, Therapy Response
Source:British Journal of Cancer
Publisher:Nature Publishing Group
Page Range:1395-1405
Date:10 April 2012
Official Publication:https://doi.org/10.1038/bjc.2012.81
PubMed:View item in PubMed

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