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Niclosamide blocks glucagon phosphorylation of serine 552 on β‐catenin leading to decrease target genes expression and improve glucose metabolism via PKA signalling pathway
Author(s) -
Chowdhury Md. Kamrul Hasan,
Morris Margaret,
Turner Nigel,
Wu Lindsay,
Shepherd Peter,
Smith Greg
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.780.4
Subject(s) - niclosamide , glucagon , phosphorylation , kinase , wnt signaling pathway , chemistry , signal transduction , medicine , endocrinology , microbiology and biotechnology , biology , biochemistry , insulin , ecology
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 this study is to determine if the effect of glucagon activating β‐catenin signalling leading to increased target gene expression is mediated through cAMP activation of protein kinase A. Primary rat hepatocytes were incubated with insulin, glucagon or epinephrine and a range of inhibitors of PI 3‐kinase, Wnt, mitochondrial uncoupler (niclosamide) or PKA inhibitors to dissection out the pathway leading to increased serine 552 phosphorylation of β‐catenin following glucagon exposure. In primary rat liver cells, we found that short exposure of glucagon or epinephrine caused a rapid increase in serine 552 phosphorylation on β‐catenin that leads to increased cyclin D1 and c‐Myc expression. Both glucose and insulin had no effect on this pathway. A range of PI 3‐kinase 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 the target genes expression. Our study also provide evidence that inhibition of the glucagon signalling pathway contributes to the beneficial effects of niclosamide (both forms of niclosamide) on whole body glucose metabolism. 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, and decrease blood glucose levels, which has recently shown promise as a potential treatment of type 2 diabetes (T2D). This novel finding could be a useful adjunctive therapeutic strategy to treat T2D, as hepatic glucose output is elevated in people with T2D and in liver cancer treatment, particularly in the context of T2D with increased β‐catenin activity. Support or Funding Information ‐ UNSW Australia, PhD scholarship ‐ Diabetes Australian Research Grant