PD0325901 Inhibition of the Erk Pathway and Effects on Pancreatic Growth

Abstract

The pancreas secretes a range of enzymes that together have the capacity to digest virtually all ingested macromolecules into forms that are capable of being absorbed. Regulated by the composition of food in the stomach, the secretion of digestive enzymes from the exocrine pancreas can be increased simultaneously at the transcriptional and translational level. However, once this finite capacity is exceeded, the pancreas must grow or regenerate in order to compensate. The extracellular signal-regulated kinase (Erk) regulates the expression of several early response genes encoding factors that regulate proliferation in many cell types. The aim of this study was to elucidate whether Erk pathway activation is necessary for pancreatic growth in a mouse model of upregulated endogenous cholecystokinin (CCK) release, a model known to stimulate pancreatic growth. In mice fed chow containing the synthetic trypsin inhibitor camostat, phosphorylation levels of Erk increased significantly in comparison to controls. The camostat-induced increase in phosphorylated Erk was blocked to levels below that of the control upon administration of the Erk inhibitor PD0325901 2 h prior to camostat feeding. In contrast, increased phosphorylation of c-Jun and S6, biomarkers of pathways believed to be required for growth, were unaffected by PD0325901. At the mRNA level, a camostat-induced increase in expression of Erk-mediated early response genes Egr-1, c- Fos, and RCAN1 were significantly blocked upon administration of PD0325901, while the upregulation of c-Jun was not affected. Chronic growth studies monitoring changes in pancreatic mass were employed; however, administration of PD0325901 resulted in the unexplained death of 3 out of 12 test subjects. Those mice which did survive illustrated varying decreases in pancreatic growth. We conclude that PD0325901 showed successful inhibition of the Erk pathway, however the necessity of the Erk pathway in pancreatic growth remains inconclusive.