Recently, it has been found that glucagon is able to activate the β-catenin signalling pathway leading to increased cyclin D1 and c-Myc expression in liver. Therefore the main aim of the present study is to determine whether the effect of glucagon activating β-catenin signalling leading to increased target gene expression is mediated through cAMP activation of PKA (protein kinase A). Primary rat hepatocytes were incubated with insulin, glucagon or adrenaline (epinephrine) and a range of inhibitors of PI3K (phosphoinositide 3-kinase), Wnt, mitochondrial uncoupler (niclosamide) or PKA inhibitors to dissect out the pathway leading to increased Ser552 phosphorylation on β-catenin following glucagon exposure. In primary rat hepatocytes, we found that short exposure to glucagon or adrenaline caused a rapid increase in Ser552 phosphorylation on β-catenin that leads to increased cyclin D1 and c-Myc expression. A range of PI3K and Wnt inhibitors were unable to block the effect of glucagon phosphorylating β-catenin. Interestingly, both niclosamide and the PKA inhibitor H89 blocked the glucagon effect on β-catenin signalling, leading to a reduction in target gene expression. Likewise, niclosamide inhibited cAMP levels and the direct addition of db-cAMP (dibutyryl-cAMP sodium salt) also resulted in Ser552 phosphorylation of β-catenin. We have identified a new pathway via glucagon signalling that leads to increased β-catenin activity that can be reversed with the antihelminthic drug niclosamide, which has recently shown promise as a potential treatment of T2D (Type 2 diabetes). This novel finding could be useful in liver cancer treatment, particularly in the context of T2D with increased β-catenin activity.
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May 2016
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The biological dimer of MurIMtb shown as a protein cartoon. Interface residues that form hydrogen bonding interactions or salt links are highlighted in purple and yellow. For further details see pp. 1267-1280. Image kindly provided by Kurt Krause. - PDF Icon PDF LinkFront Matter
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Research Article|
April 26 2016
Niclosamide blocks glucagon phosphorylation of Ser552 on β-catenin in primary rat hepatocytes via PKA signalling
Md. Kamrul H. Chowdhury;
Md. Kamrul H. Chowdhury
*Department of Pharmacology, UNSW Australia, Sydney, NSW 2052, Australia
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Lindsay E. Wu;
Lindsay E. Wu
*Department of Pharmacology, UNSW Australia, Sydney, NSW 2052, Australia
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James L.J. Coleman;
James L.J. Coleman
†Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia
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Nicola J. Smith;
Nicola J. Smith
†Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia
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Margaret J. Morris;
Margaret J. Morris
*Department of Pharmacology, UNSW Australia, Sydney, NSW 2052, Australia
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Peter R. Shepherd;
Peter R. Shepherd
‡Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
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Greg C. Smith
Greg C. Smith
1
*Department of Pharmacology, UNSW Australia, Sydney, NSW 2052, Australia
1To whom correspondence should be addressed (email g.smith@unsw.edu.au).
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Publisher: Portland Press Ltd
Received:
November 10 2015
Revision Received:
March 09 2016
Accepted:
March 10 2016
Accepted Manuscript online:
March 10 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (9): 1247–1255.
Article history
Received:
November 10 2015
Revision Received:
March 09 2016
Accepted:
March 10 2016
Accepted Manuscript online:
March 10 2016
Citation
Md. Kamrul H. Chowdhury, Lindsay E. Wu, James L.J. Coleman, Nicola J. Smith, Margaret J. Morris, Peter R. Shepherd, Greg C. Smith; Niclosamide blocks glucagon phosphorylation of Ser552 on β-catenin in primary rat hepatocytes via PKA signalling. Biochem J 1 May 2016; 473 (9): 1247–1255. doi: https://doi.org/10.1042/BCJ20160121
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