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.