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Cholecystokinin Receptor Antagonist Induces Pancreatic Stellate Cell Plasticity Rendering the Tumor Microenvironment
Gurbani Jolly1, Tetyana Duka2, Narayan Shivapurkar2
1Department of Oncology, College of Medicine, Georgetown University, Washington, DC 20007, USA.
Abstract:
CCK receptors are expressed on pancreatic cancer epithelial cells, and blockade with receptor antagonists decreases tumor growth. Activated pancreatic stellate cells or myofibroblasts have also been described to express CCK receptors, but the contribution of this novel pathway in fibrosis of the pancreatic cancer microenvironment has not been studied. We examined the effects of the nonselective CCK receptor antagonist proglumide on the activation, proliferation, collagen deposition, differential expression of genes, and migration in both murine and human PSCs. CCK receptor expression was examined using western blot analysis. Collagen production using activated PSCs was analyzed by mass spectroscopy and western blot. Migration of activated PSCs was prevented in vitro by proglumide and the CCK-B receptor antagonist, L365,260, but not by the CCK-A receptor antagonist L365,718. Proglumide effectively decreased the expression of extracellular matrix-associated genes and collagen-associated proteins in both mouse and human PSCs. Components of fibrosis, including hydroxyproline and proline levels, were significantly reduced in PSC treated with proglumide compared to controls. CCK peptide stimulated mouse and human PSC proliferation, and this effect was blocked by proglumide. These investigations demonstrate that targeting the CCK-B receptor signaling pathway with proglumide may alter the plasticity of PSC, rendering them more quiescent and leading to a decrease in fibrosis in the pancreatic cancer microenvironment.
Insights
Targeting cholecystokinin (CCK) receptors on pancreatic stellate cells with proglumide may reduce pancreatic cancer fibrosis. This CCK-B receptor blockade decreases collagen deposition and PSC proliferation, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Gastroenterology
- Cell Biology
Background:
- Cholecystokinin (CCK) receptors are present on pancreatic cancer cells, and their antagonists inhibit tumor growth.
- Pancreatic stellate cells (PSCs) also express CCK receptors, but their role in pancreatic cancer-associated fibrosis is unstudied.
Purpose of the Study:
- To investigate the effects of the CCK receptor antagonist proglumide on pancreatic stellate cell activation, proliferation, and collagen deposition.
- To determine the specific CCK receptor subtype involved in PSC activation and migration.
Main Methods:
- Western blot analysis for CCK receptor expression.
- Mass spectrometry and western blot for collagen production.
- In vitro assays for PSC proliferation and migration.
- Analysis of hydroxyproline and proline levels.
Main Results:
- Proglumide and a CCK-B receptor antagonist inhibited PSC migration, while a CCK-A antagonist did not.
- Proglumide significantly reduced extracellular matrix gene expression and collagen proteins in PSCs.
- CCK peptide-induced PSC proliferation was blocked by proglumide.
- Hydroxyproline and proline levels, indicative of fibrosis, were decreased by proglumide treatment.
Conclusions:
- Targeting the CCK-B receptor signaling pathway with proglumide may modulate PSC plasticity towards a quiescent state.
- This blockade could lead to reduced fibrosis within the pancreatic cancer microenvironment.
- Proglumide presents a potential therapeutic strategy for pancreatic cancer by targeting stromal components.
