Abstract
Inflammation and acinar cell necrosis are two major pathological responses of acute pancreatitis, a serious disorder with no current therapies directed to its molecular pathogenesis. Serine/threonine protein kinase D family, which includes PKD/PKD1, PKD2, and PKD3, has been increasingly implicated in the regulation of multiple physiological and pathophysiological effects. We recently reported that PKD/PKD1, the predominant PKD isoform expressed in rat pancreatic acinar cells, mediates early events of pancreatitis including NF-κB activation and inappropriate intracellular digestive enzyme activation. In current studies, we investigated the role and mechanisms of PKD/PKD1 in the regulation of necrosis in pancreatic acinar cells by using two novel small molecule PKD inhibitors CID755673 and CRT0066101 and molecular approaches in in vitro and in vivo experimental models of acute pancreatitis. Our results demonstrated that both CID755673 and CRT0066101 are PKD-specific inhibitors and that PKD/PKD1 inhibition by either the chemical inhibitors or specific PKD/PKD1 siRNAs attenuated necrosis while promoting apoptosis induced by pathological doses of cholecystokinin-octapeptide (CCK) in pancreatic acinar cells. Conversely, up-regulation of PKD expression in pancreatic acinar cells increased necrosis and decreased apoptosis. We further showed that PKD/PKD1 regulated several key cell death signals including inhibitors of apoptotic proteins, caspases, receptor-interacting protein kinase 1 to promote necrosis. PKD/PKD1 inhibition by CID755673 significantly ameliorated necrosis and severity of pancreatitis in an in vivo experimental model of acute pancreatitis. Thus, our studies indicate that PKD/PKD1 is a key mediator of necrosis in acute pancreatitis and that PKD/PKD1 may represent a potential therapeutic target in acute pancreatitis.
Highlights
Pancreatic acinar cell necrosis is a major pathological response of acute pancreatitis associated with significant morbidity and mortality from the disease (Gukovskaya and Pandol, 2004; Pandol et al, 2007)
PKD/PKD1 REGULATES CELL DEATH PATHWAYS IN PANCREATIC ACINAR CELLS – PROMOTING CELL NECROSIS AND SUPPRESSING APOPTOSIS AND CASPASE ACTIVATION We investigated the role of PKD/PKD1 in death pathways by examining the effect of the two PKD inhibitors on cell necrosis and apoptosis death pathways in pancreatic acinar cells stimulated with a supramaximal dose of CCK, which serves as an in vitro experimental pancreatitis model (Figure 2)
The studies presented here demonstrate that PKD/PKD1 activation promotes necrosis and inhibits apoptosis in both in vitro and in vivo models of pancreatitis
Summary
Pancreatic acinar cell necrosis is a major pathological response of acute pancreatitis associated with significant morbidity and mortality from the disease (Gukovskaya and Pandol, 2004; Pandol et al, 2007). Apoptosis and necrosis are two major forms of acinar cell death in acute pancreatitis and associated with specific morphological and biochemical features (Gukovskaya and Pandol, 2004; Mareninova et al, 2006). PKD1 regulates death-signaling in pancreatitis acinar cell death (i.e., apoptosis versus necrosis) in pancreatitis will provide potential molecular targets for therapy in this disease. We recently reported that PKD/PKD1 mediates NF-κB activation and inappropriate intracellular digestive enzyme activation in pancreatitis (Yuan et al, 2008; Thrower et al, 2011) Despite of these studies, the role of PKD/PKD1 in another critical pathological response in pancreatitis, acinar cell necrosis, has not been investigated. PKD/PKD1 is a potential therapeutic target in acute pancreatitis
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