| Project/Area Number |
15591408
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Okayama University |
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Principal Investigator |
IWAGAKI Hiromi Okayama University, hospital, lecturer, 医学部・歯学部附属病院, 講師 (50240867)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIBORI Masahiro Okayama University, Graduate School of Medicine and Dentistry, professor, 大学院・医歯学総合研究科, 教授 (50135943)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | protease-activated-receptor / serine-protease / thrombin / trypsin / PAR-1 / PAR-2 / DIC / cell-growth / プロテアーゼ活性化受容体 / 大腸癌細胞 / PKC / MAP kinase |
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| Research Abstract |
We found that tryptase-positive mast cells were abundant in the invasive front of the human colon adenocarcinoma by examining 30 cases. Because tryptase has been suggested to be agonist proteinase for protease-activated receptor-2(PAR-2), we investigated the effects of stimulation of PAR-2 by tryptase on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line. PAR-2 stimulation by tryptase induced the increase in [Ca2+]I, whitch was desensitized by the prior application of PAR-2 activating peptide but not by PAR-1 agonist peptide. The proliferative responses of DLD-1 to tryptase and PAR-2 activating peptide were associated with the phosphorylation of MEK and MAP kinase, but not p38 MAPkinase and Junk. Inhibition of MEK by PD98059 completely inhibited the proliferation-enhancing effects of tryptase and PAR-2 agonist peptide as well as phosphorylation of MAP kinase. Moreover, tryptase and PAR-2 activating peptide stimulated the production of prostaglandin E2 and the inhibition of prostaglandin synthesis by indomethacin or NS398 resulted in the complete inhibition of the proliferative response to tryptase and PAR-2 AP. Furthermore, the tryptase-stimulated proliferation of DLD-1 was concentration-dependently inhibited by nafamostat mesilate, a specific inhibitor of tryptase. These results as a whole indicated that tryptase has proliferative effects on DLD-1 carcinoma cell through COX-and MAP kinase-dependent manners acting on PAR-2 by its proteolytic activity.
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