Jolly Gurbani, Duka Tetyana, Shivapurkar Narayan, Chen Wenqiang, Bansal Sunil, Cheema Amrita, Smith Jill P
Department of Oncology, College of Medicine, Georgetown University, Washington, DC 20007, USA.
Department of Medicine, College of Medicine, Georgetown University, Washington, DC 20007, USA.
Cancers (Basel). 2023 May 18;15(10):2811. doi: 10.3390/cancers15102811.
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.
CCK受体在胰腺癌上皮细胞上表达，用受体拮抗剂阻断可降低肿瘤生长。也有研究表明，活化的胰腺星状细胞或肌成纤维细胞表达CCK受体，但这一新途径在胰腺癌微环境纤维化中的作用尚未得到研究。我们研究了非选择性CCK受体拮抗剂丙谷胺对小鼠和人胰腺星状细胞（PSC）的活化、增殖、胶原沉积、基因差异表达及迁移的影响。采用蛋白质印迹分析检测CCK受体表达。通过质谱和蛋白质印迹分析活化PSC的胶原产生情况。丙谷胺和CCK-B受体拮抗剂L365,260可在体外阻止活化PSC的迁移，但CCK-A受体拮抗剂L365,718则无此作用。丙谷胺可有效降低小鼠和人PSC中细胞外基质相关基因及胶原相关蛋白的表达。与对照组相比，用丙谷胺处理的PSC中包括羟脯氨酸和脯氨酸水平在内的纤维化成分显著降低。CCK肽可刺激小鼠和人PSC增殖，而丙谷胺可阻断这一作用。这些研究表明，用丙谷胺靶向CCK-B受体信号通路可能会改变PSC的可塑性，使其更趋于静止，从而减少胰腺癌微环境中的纤维化。
