PKD signaling and pancreatitis

Abstract

Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder.

Novel Small Molecule Inhibitors of Protein Kinase D Suppress NF-kappaB Activation and Attenuate the Severity of Rat Cerulein Pancreatitis

“…Small chemical inhibitors of PKD have significant potential as therapeutic intervention for pancreatitis through blocking NF-κB activation, a critical early pathological event in this disease. Combining with our previous reports (Yuan et al, 2008 , 2012 ; Thrower et al, 2011 ; Yuan and Pandol, 2016 ) that identified PKD as an early convergent target of PKCδ and ε signaling in NF-κB activation in exocrine pancreas, we summarized our findings in Figure 8 to show the signaling pathways of PKD mediating NF-κB activation in pancreatitis. In addition, we here also presented/summarized the overall role of PKD, which we found so far, in multiple pathological processes associated with pancreatitis (Figure 8 ).…”

“…PKDs can be activated by a numbers of gastrointestinal secretagogues in pancreatic acini (Berna et al, 2007 ; Yuan et al, 2008 , 2012 ; Chen et al, 2009 ; Thrower et al, 2011 ; Yuan and Pandol, 2016 ). Our studies showed that the peptide hormone cholecystokinin 8 (CCK) and the cholinergic agonist carbachol (CCh) induced a dose-dependent rapid activation of PKD in pancreatic acini, which was closely correlated with increased NF-κB activity (Yuan et al, 2008 ).…”

“…Two research groups have reported the in vitro and in vivo anti-tumor growth effect of the inhibitors in pancreatic ductal adenocarcinoma and prostate cancer respectively (Sharlow et al, 2008 ; Harikumar et al, 2010 ). Of significant importance for pancreatitis, we have reported that CRT0066101 reduces secretagogues-induced zymogen premature activation in primary pancreatic acini (Thrower et al, 2011 ) and that CID755673 treatment attenuates pancreatic necrotic death in cerulein-induced experimental pancreatitis models (Yuan et al, 2012 ; Yuan and Pandol, 2016 ). The aims of the current study are to explore (1) whether the novel PKD inhibitors block NF-κB activation in experimental pancreatitis models, and (2) whether suppressing of NF-κB activation by the PKD inhibitors is associated with attenuation of inflammatory response and severity of pancreatitis, as well as (3) the therapeutic benefit of the PKD inhibitors administered after induction of the pancreatitis.…”

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

“…Nevertheless, the superior efficacy of Compound A in human islets in low glucose conditions suggests that Compound A administration might lead to hypoglycemia and activation of Ga12/13 could be contraindicated to avoid insulin secretion in low glucose conditions. Moreover, in addition to its role in insulin secretion, PKD activation has been linked to NF-kB activation, the development of inflammation, and pancreatitis (Yuan and Pandol, 2016). Although GPR40 does not seem expressed in the exocrine pancreas, it would be interesting to assess whether Compound A could yield inflammatory responses after either acute or chronic treatment.…”

Dachengqi Decoction Attenuates Intestinal Vascular Endothelial Injury in Severe Acute Pancreatitis in Vitro and in Vivo

“…SAP is due to trypsinogen activation, which leads to inflammatory response including autodigestion, edema, hemorrhage, and even necrosis of the pancreas [1-3]. The pathogenic mechanism of SAP has not been fully investigated whatever the cause.…”