Protein kinase D regulates cell death pathways in experimental pancreatitis
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 i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2012-03-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00060/full |
| _version_ | 1818173984836943872 |
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| author | Jingzhen eYuan Jingzhen eYuan Yannan eLiu Yannan eLiu Tanya eTan Tanya eTan Sushovan eGuha Ilya eGukovsky Ilya eGukovsky Anna eGukovskaya Anna eGukovskaya Stephen J Pandol Stephen J Pandol |
| author_facet | Jingzhen eYuan Jingzhen eYuan Yannan eLiu Yannan eLiu Tanya eTan Tanya eTan Sushovan eGuha Ilya eGukovsky Ilya eGukovsky Anna eGukovskaya Anna eGukovskaya Stephen J Pandol Stephen J Pandol |
| author_sort | Jingzhen eYuan |
| collection | DOAJ |
| description | 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-kappaB 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, upregulation 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 (IAPs), caspases, receptor-interacting protein kinase 1 (RIP1) 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. |
| first_indexed | 2024-12-11T19:37:12Z |
| format | Article |
| id | doaj.art-47ca1a3abc694b2e8b3871009b994396 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-11T19:37:12Z |
| publishDate | 2012-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-47ca1a3abc694b2e8b3871009b9943962022-12-22T00:53:08ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2012-03-01310.3389/fphys.2012.0006023026Protein kinase D regulates cell death pathways in experimental pancreatitisJingzhen eYuan0Jingzhen eYuan1Yannan eLiu2Yannan eLiu3Tanya eTan4Tanya eTan5Sushovan eGuha6Ilya eGukovsky7Ilya eGukovsky8Anna eGukovskaya9Anna eGukovskaya10Stephen J Pandol11Stephen J Pandol12University of California Los AngeleVeterans Affairs Greater Los Angeles Healthcare SystemUniversity of California Los AngeleBeijing HospitalUniversity of California Los AngeleVeterans Affairs Greater Los Angeles Healthcare SystemUniversity of Texas M.D. Anderson Cancer CenterUniversity of California Los AngeleVeterans Affairs Greater Los Angeles Healthcare SystemUniversity of California Los AngeleVeterans Affairs Greater Los Angeles Healthcare SystemUniversity of California Los AngeleVeterans Affairs Greater Los Angeles Healthcare SystemInflammation 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-kappaB 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, upregulation 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 (IAPs), caspases, receptor-interacting protein kinase 1 (RIP1) 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.http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00060/fullApoptosisNecrosischolecystokinin-octapeptideCID755673pancreatic acinar cells |
| spellingShingle | Jingzhen eYuan Jingzhen eYuan Yannan eLiu Yannan eLiu Tanya eTan Tanya eTan Sushovan eGuha Ilya eGukovsky Ilya eGukovsky Anna eGukovskaya Anna eGukovskaya Stephen J Pandol Stephen J Pandol Protein kinase D regulates cell death pathways in experimental pancreatitis Frontiers in Physiology Apoptosis Necrosis cholecystokinin-octapeptide CID755673 pancreatic acinar cells |
| title | Protein kinase D regulates cell death pathways in experimental pancreatitis |
| title_full | Protein kinase D regulates cell death pathways in experimental pancreatitis |
| title_fullStr | Protein kinase D regulates cell death pathways in experimental pancreatitis |
| title_full_unstemmed | Protein kinase D regulates cell death pathways in experimental pancreatitis |
| title_short | Protein kinase D regulates cell death pathways in experimental pancreatitis |
| title_sort | protein kinase d regulates cell death pathways in experimental pancreatitis |
| topic | Apoptosis Necrosis cholecystokinin-octapeptide CID755673 pancreatic acinar cells |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00060/full |
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