Role of protein kinase D signaling in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal survival rates. Its intransigence to conventional therapy renders PDAC an aggressive disease with early metastatic potential. Thus, novel targets for PDAC therapy are urgently needed. Multiple signal transduction pathways are implicated in progression of PDAC. These pathways stimulate production of intracellular messengers in their target cells to modify their behavior, including the lipid-derived diacylglycerol (DAG). One of the prominent intracellular targets of DAG is the protein kinase C (PKC) family. However, the mechanisms by which PKC-mediated signals are decoded by the cell remain incompletely understood. Protein kinase D1 (PKD or PKD1, initially called atypical PKCμ), is the founding member of a novel protein kinase family that includes two additional protein kinases that share extensive overall homology with PKD, termed PKD2, and PKD3. The PKD family occupies a unique position in the signal transduction pathways initiated by DAG and PKC. PKD lies downstream of PKCs in a novel signal transduction pathway implicated in the regulation of multiple fundamental biological processes. We and others have shown that PKD-mediated signaling pathways promote mitogenesis and angiogenesis in PDAC. Our recent observations demonstrate that PKD also potentiates chemoresistance and invasive potential of PDAC cells. This review will briefly highlight diverse biological roles of PKD family in multiple neoplasias including PDAC. Further, this review will underscore our latest advancement with the development of a potent PKD family inhibitor and its effect both in vitro and in vivo in PDAC.
Guha
Sushovan
S
Department of Gastroenetrology, Hepatology, and Nutrition, the UT MD Anderson Cancer Center, Unit 1466, 1515 Holcombe Boulevard, Houston, TX 77030, USA. sguha@mdanderson.org
Tanasanvimon
Suebpong
S
Sinnett-Smith
James
J
Rozengurt
Enrique
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000502:physiology; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000502:physiology; D015398:Signal Transduction
D000970:Antineoplastic Agents; D006360:Heat-Shock Proteins; D000091283:Protein Kinase D2; D011494:Protein Kinases; C119190:protein kinase C nu; C089212:protein kinase D; D011493:Protein Kinase C