Glucagon phosphorylates serine 552 ofβ-catenin leading to increased expression of cyclin D1 and c-Myc in the isolated rat liver

Abstract

In the last 20 years the prevalence of metabolic disorders, in particular type 2 diabetes (T2D), has more than doubled. Recently, a strong link between T2D and cancer, in particularly liver cancer has been reported. However, the mechanism connecting the development of type 2 diabetes and cancer remains unknown. One of the biggest drivers of liver cancer is alterations in the Wnt/β-catenin pathway. In this study, we aimed to identify the effect of glucagon on β-catenin in the isolated rat liver. We found glucagon, which is substantially raised in patients with T2D, rapidly phosphorylates β-catenin on serine 552 that is associated with increased expression of genes cyclin D1 (CCND1) and c-Myc (MYC), which are known to be involved in liver cancer. This finding may explain the increased risk of liver cancer in people with T2D.

Niclosamide reduces glucagon sensitivity via hepatic PKA inhibition in obese mice: Implications for glucose metabolism improvements in type 2 diabetes

“…Interestingly, they also reported a significant reduction in hepatic glucose production during a gold standard clamp experiment19. This supports our findings that both NENS and Nic block the effect of glucagon in the liver that is the major driver of hepatic glucose production1735. Although we did not find evidence of increased energy expenditure with either NENS or Nic as stated by Tao et al 19.…”

“…β-catenin-92 kDa and CREB-43 kDa). The membranes were incubated for 1 h in blocking buffer (20 mM Tris; pH 7.4), 137 mM NaCl, 0.5% (v/v) Tween 20 containing 4% (w/v) BSA (ICP Bio, Auckland, New Zealand) at room temperature and then incubated at 4 °C overnight in blocking buffer containing primary β-catenin antibody (pS552 and total; 1:1000; Cell Signaling Technology, Danvers, MA, USA), CREB antibody (pS133; 1:1000; Cell Signaling Technology, Danvers, MA, USA) and GAPDH antibody (1:1000; Cell Signaling Technology, Danvers, MA, USA) which we have validated and published previously171821. Immunoreactive proteins were detected using horseradish peroxidase-linked secondary antibody (1:1000; Cell Signaling Technology, Danvers, MA, USA) and enhanced chemiluminescence (ECL) according to the manufacturer’s instructions (BIO-RAD, Hercules, CA, USA).…”

“…Both NENS and Nic uncouple mitochondria, which would lead to reduced ATP formation and based on our in vitro data, would block PKA signalling which is an essential component of the glucagon signalling pathway1718. Therefore, we tested the effect of NENS or Nic on glucagon responses in a terminal study in mice exposed to vehicle or glucagon for 15 minutes before cervical dislocation and rapid liver collection.…”

“…Recently, we identified novel glucagon responses in isolated rat liver showing that glucagon rapidly increases hepatic glucose production (HGP) and phosphorylates serine 552 on β-catenin, thereby increasing targeted β-catenin/TCF7L2 gene expression17. The effect was reversed by niclosamide, a drug used to treat intestinal infections of tapeworms in humans by uncoupling the mitochondria, by blocking glucagon induced PKA activation via cAMP signalling18.…”

Skin renewal activity of non-thermal plasma through the activation of β-catenin in keratinocytes

“…The homophilic interaction of E-cadherins from neighboring cells stimulates the formation of an adherence junctional complex that includes α, β-catenin on its intracellular domain to form cell cytoskeleton 17 . Importantly, β-catenin is a key factor in the wnt signaling pathway and acts as a transcriptional regulator that promotes the expression of cell proliferation genes such as cyclin D1 and c-MYC 18–20 .…”