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: Kristin K Fino, Gail L Matters, Christopher O McGovern, Evan L Gilius, Jill P Smith
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 302 Issue 11 Pg. G1244-52 (Jun 01 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22442157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptor, Cholecystokinin B
• X-Linked Inhibitor of Apoptosis Protein
• Caspase 3

Topics

• Apoptosis (genetics)
• Caspase 3 (genetics, metabolism)
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Pancreas (metabolism)
• Pancreatic Neoplasms (genetics, metabolism)
• RNA Interference
• Receptor, Cholecystokinin B (genetics, metabolism)
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)