Elander N, Ungerbäck J, Olsson H, Uematsu S, Akira S, Söderkvist P
Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden.
Biochem Biophys Res Commun. 2008 Jul 18;372(1):249-53. doi: 10.1016/j.bbrc.2008.05.026. Epub 2008 May 15.
The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H(2) (PGH(2)) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APC(Min/+) mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH(2) into PGE(2), surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p<0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p<0.0005). No deviation regarding the expression of other PGE(2) related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE(2) levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH(2) derived prostanoids were generally enhanced, being most prominent for TxA(2) and PGD(2). Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE(2) during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer.
环氧合酶-2（COX-2）和前列腺素H2（PGH2）下游生物活性前列腺素的诱导合成在结直肠癌发生过程中发挥着关键作用。在此，我们证明，微粒体前列腺素E合酶-1（mPGES-1）基因缺失的APC（Min/+）小鼠，该酶催化PGH2最终转化为PGE2，令人惊讶的是，其发生的肠道肿瘤比mPGES-1野生型同窝小鼠更多且通常更大（平均肿瘤数/肠道：80对38，p<0.0005；平均肿瘤直径：1.64对1.12mm，p<0.0005）。在mPGES-1缺陷小鼠中，其他与PGE2相关的酶（COX-1、COX-2、mPGES-2、cPGES和15-PGDH）或受体（EP1-4）的表达没有明显偏差。mPGES-1缺陷动物肿瘤中的PGE2水平受到抑制，但其他PGH2衍生的前列腺素浓度普遍升高，以血栓素A2（TxA2）和前列腺素D2（PGD2）最为显著。因此，我们推测在肠道肿瘤发生过程中，向其他脂质介质的重新定向合成可能（过度）补偿mPGES-1/PGE2的缺失。然而，我们的结果质疑了mPGES-1靶向治疗在结直肠癌治疗或预防中的适用性。
