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.
Niclosamide blocks glucagon phosphorylation of Ser552 on β-catenin in primary rat hepatocytes via PKA signalling
- Views Icon Views
- Share Icon Share
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
Download citation file: