Analyses of pathophysiological functions of prostaglandin E synthases as a potential target for novel anti-inflammatory drugs

本研究利用mPGES-1基因敲除小鼠研究了花生四烯酸代谢中PGE_2生物合成末端酶PGE_2合酶（mPGES-1）的病理生理作用. mPGES-1与癌症：稳定过表达mPGES-1的Luwis肺癌（LLC）细胞在体外增殖更快，当植入C57 BL/6小鼠时，形成比亲本细胞更大、更多的皮下肿瘤和肺转移灶。相反，mPGES敲低的LLC细胞在植入小鼠中产生更小和更少的肿瘤。与复制的野生型小鼠相比，植入LLC细胞的mPGES-1缺失小鼠显示出与减少的血管生成相关的对肿瘤生长和转移的抗性。此外，与野生型小鼠相比，mPGES-1基因敲除小鼠中氧化偶氮甲烷诱导的结肠癌发生显著减少。1在肿瘤细胞和宿主组织中表达，参与肿瘤发生. mPGES-1和炎症：在角叉菜胶和巯基乙酸诱导的腹膜炎模型中，mPGES-1缺陷小鼠的白细胞浸润与对照小鼠相比明显减轻. mPGES-1和骨：在小鼠骨骼疾病模型中，mPGES-1缺乏与骨折愈合受损有关，但与骨丢失或骨关节炎无关. mPGES-1和结肠炎：与对照组小鼠相比，mPGES-1基因敲除小鼠的结肠炎（一种炎症性肠病模型）明显加重，因此，抑制mPGES-1的新药将用于癌症和炎症的治疗，但可能对骨骼和胃肠道产生一些不良影响。

In this study, we examined the pathophysiological roles of PGE_2 synthase (mPGES-1), a terminal PGE_2-biosynthetic enzyme in the arachidonic acid metabolism, using mPGES-1 knockout mice.1. mPGES-1 and cancer : Luwis lung carcinoma (LLC) cells stably overexpressing mPGES-1 proliferated more rapidly in vitro and, when implanted into C57BL/6 mice, formed larger and more subcutaneous tumors and lung metastatic foci than did parental cells. Conversely, mPGES-knockdown LLC cells produced smaller and fewer tumors in implanted mice mPGES-1-null mice implanted with LLC cells showed resistance to tumor growth and metastasis associated with reduced angiogenesis compared with replicate wild-type mice Moreover, azoxymethanie-induced colon carcinogenesis was markedly reduced in mPGES-1-null mice relative to that in wild-type mice These results indicate that mPGES-1 expressed in tumor cells as well as in host tissues participates in tumorigenesis.2. mPGES-1 and inflammation : In carageenan- and thioglycolate-induced peritonitis models, leukocyte infiltration was markedly mitigated in mPGES-1-deficient mice as compared with that m control mice.3. mPGES-1 and bone : mPGES-1 deficiency was associated with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders.4. mPGES-1 and colitis : Dextran sulfate-induced colitis (a model of inflammatory bowel disease), as evaluated by intestinal histology, bleeding and cytokine expression, was significantly exacerbated in mPGES-1 knockout mice compared with control mice.Thus, novel drugs that could inhibit mPGES-1 would be useful for treatments of cancer and inflammation, yet they might have some adverse effects on bone and gastrointestinal tract.