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

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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.