Background: Pancreatic cancer has a dismal prognosis with only 1% surviving 5 years. Reasons for this poor prognosis include the inability to diagnosis pancreatic cancer in early stages and its resistance to standard chemotherapy. The gastrointestinal peptide, gastrin, has been identified as a growth factor in pancreatic cancer. Gastrin stimulates growth of pancreatic cancer through the cholecystokinin (CCK)-B receptor and a splice variant of this receptor (CCK-C), which is expressed only in cancer cells.

Hypothesis: It is hypothesized that down regulation of the gastrin binding receptors, CCK-B/C, by small interfering RNAs (siRNAs) will inhibit growth of pancreatic cancer.

Methods: A series of human pancreatic cancer cells were screened by Real-Time RT-PCR for the presence and quantity of CCK-B/C receptor mRNA. Receptor binding was identified in pancreatic cancer cells with a CCK-B polyclonal antibody (1:10,000) by immunocytochemistry. PANC-1 cells were transfected with siRNAs that target a region of mRNA common to both the CCK-B and CCK-C receptor with either Lipofectamine 2000 or pegylated cationic nanoliposomes previously shown to be nontoxic after systemic intravenous administration. RNA was extracted and analyzed by TaqMan Real-Time RT-PCR for the receptor expression 3 days after treatment. Control cells were untreated, vehicle only treated (Lipofectamine 2000 or pegylated cationic nanoliposomes), or treated with a scrambled siRNA control. The effects of CCK-B/C knock-down on growth were evaluated by counting cells at various time points by trypan blue dye exclusion.

Results: The CCK-B/C receptor was detected in several human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, AsPC-1, BxPC-3, and Capan-1) by Real-Time RT-PCR. The receptor was identified by immunofluorescence in the plasma membrane. CCK-B/C receptor expression was down regulated by CCK-B/C siRNA with both Lipofectamine 2000 and pegylated cationic nanoliposomes. PANC-1 cell growth was significantly decreased in CCK-B/C receptor targeted siRNA treated cells compared to untreated cells, vehicle only, and scrambled control on day 3 (p<0.0001, n=9). Control cells more than doubled in number while CCK-B/C siRNA treated cells increased by only 10%.

Conclusion: The CCK-B/C receptor is present in human pancreatic cancer cells and knock-down significantly decreases cell growth. Systemic administration of CCK-B/C siRNAs by pegylated cationic nanoliposomes may be a potential therapeutic modality for pancreatic cancer.

Supported by NIH CA117926.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4132.