title: Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis.
abstract: Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor (CCK-BR), which has been found to be overexpressed in pancreatic cancer. In this study, we proposed that the CCK-BR drives growth of pancreatic cancer; hence, interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics. The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents. The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA, respectively, and the effects on cell growth and apoptosis were assessed. CCK-BR downregulation resulted in reduced cancer cell proliferation, decreased DNA synthesis, and cell cycle arrest as demonstrated by an inhibition of G(1) to S phase progression. Furthermore, CCK-BR downregulation increased caspase-3 activity, TUNEL-positive cells, and decreased X-linked inhibitor of apoptosis protein expression, suggesting apoptotic activity. Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated, as assessed by a migration assay. These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer. Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer.
authors.affiliation: Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, 17033, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Fino
authors.forename: Gail L
authors.initials: GL
authors.lastname: Matters
authors.forename: Christopher O
authors.initials: CO
authors.lastname: McGovern
authors.forename: Evan L
authors.initials: EL
authors.lastname: Gilius
authors.forename: Jill P
authors.initials: JP
authors.lastname: Smith
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010179:Pancreas / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D043887:Receptor, Cholecystokinin B / Q000235:genetics* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D043887:Receptor, Cholecystokinin B; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3