A role of G-protein coupled receptor-mediated signal transduction on growth, invasion and antiapoptosis of human pancreatic cancer cells

近年来，血管紧张素II（angiotensin II，Ang II）、胰蛋白酶和溶血磷脂酸（lysophosphatidic acid，LPA）等特异性G蛋白偶联受体（AT 1，PAR-2，EDG-2，-4）的激活，可诱导G蛋白介导的信号转导，参与炎症、肿瘤等多种生理病理过程，引起了人们的广泛关注。本研究的目的是探讨肿瘤源性血管紧张素II，胰蛋白酶和LPA是否通过其特异性G蛋白偶联受体在人胰腺癌的增殖和生存中起重要作用。结果，研究的所有三种胰腺癌细胞系（AsPC-1、BxPC-3和Panc-1），从分化良好到分化不良的类型，均显示出AT 1、PAR-2和EDG-2、-4受体的中度至强烈表达。至于胰腺癌细胞的信号传导，血管紧张素II和胰蛋白酶甚至在100 nM或更低的浓度下通过MAP激酶活化刺激胰腺癌细胞的生长，并通过NF-κ B活化和随后的抗凋亡分子（包括Survivin和Bcl-XL）的产生防止顺铂（CDDP）诱导的凋亡。LPA浓度低于1 μM时对胰腺癌细胞生长无明显刺激作用。总之，这表明，不仅肿瘤来源的血管紧张素II，而且肿瘤来源的胰蛋白酶必须是一个非常有效的促分裂剂，并在AT 1阳性和/或PAR-2阳性胰腺癌细胞的生长和耐药性中发挥关键作用。阐明由肿瘤源性血管紧张素II和/或胰蛋白酶激活的信号转导机制可能会深入了解胰腺癌生长和化疗耐药性的分子机制，并最终导致新的化疗。

Recently, angiotensin II (Ang II), trypsin and lysophosphatidic acid (LPA) has attracted considerable attention because activation of their specific G-protein-coupled receptors (AT1, PAR-2, and EDG-2,-4) can induce G protein-mediated signal transduction and is involved in a number of physiologic and pathologic processes such as inflammation and tumor progression. The purpose of this study was to investigate whether tumor-derived angiotensin II, trypsin and LPA plays an important role in the proliferation and survival of human pancreatic cancers through their specific G-protein-coupled receptors. As a result, all three pancreatic cancer cell lines (AsPC-1, BxPC-3, and Panc-1) studied, from well to poorly differentiated types, showed a moderate to strong expression of AT1, PAR-2 and EDG-2,-4 receptors. As to the signal transduction of pancreatic cancer cells, angiotensin II and trypsin stimulated the growth of pancreatic cancer cells even at the concentration of 100 nM or less through MAP kinase activation, and prevented cisplatin (CDDP)-induced apoptosis through NF-kB activation and the subsequent production of anti-apoptotic molecules, including Survivin and Bcl-XL. However, LPA did not stimulated the growth of pancreatic cancer cells at the concentration of less than 1 μM. In summary, it is suggested that not only tumor-derived angiotensin II but also tumor-derived trypsin must be a very potent mitogen and play a pivotal role in the growth and chemoresistance of AT1-positive and/or PAR-2 positive pancreatic cancer cells. Elucidation of the signal transduction machinery activated by tumor-derived angiotensin II and/or trypsin may provide insight into the molecular mechanisms underlying growth and chemoresistance of pancreatic cancers and ultimately lead to novel chemotherapies.