1. Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis
- Author
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Yoshihito Nakatani, Yukio Ishikawa, Toshiharu Ishii, Ichiro Kudo, Yuka Sasaki, Daisuke Kamei, Shizuo Akira, Masataka Majima, Makoto Murakami, Satoshi Uematsu, and Shuntaro Hara
- Subjects
Small interfering RNA ,dmPGE2, 16,16-dimethyl prostaglandin E2 ,medicine.medical_treatment ,medicine.disease_cause ,Biochemistry ,EP, prostaglandin E receptor ,Metastasis ,Mice ,Neoplasms ,cPGES, cytosolic prostaglandin E synthase ,Prostaglandin E2 ,NSAID, non-steroidal anti-inflammatory drug ,Neoplasm Metastasis ,mPGES, microsomal prostaglandin E synthase ,Prostaglandin-E Synthases ,Mice, Knockout ,DMEM, Dulbecco's modified Eagle's medium ,PGES, PGE synthase ,VEGF, vascular endothelial growth factor ,TBS-Tween, TBS containing 0.05% Tween 20 ,ECM, extracellular matrix ,MMP, matrix metalloproteinase ,Intramolecular Oxidoreductases ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,RT, reverse transcriptase ,lipids (amino acids, peptides, and proteins) ,Metabolic Networks and Pathways ,medicine.drug ,Prostaglandin E ,Research Article ,musculoskeletal diseases ,medicine.medical_specialty ,Biology ,microsomal prostaglandin E synthase-1 ,Dinoprostone ,COX, cyclo-oxygenase ,HEK, human embryonic kidney ,Internal medicine ,Microsomes ,medicine ,metastasis ,Animals ,Neoplasm Invasiveness ,PG, prostaglandin ,Molecular Biology ,Cell Proliferation ,KD, knockdown ,prostaglandin E2 ,KO, knockout ,Cell growth ,Lewis lung carcinoma ,Cell Biology ,medicine.disease ,WT, wild-type ,TBS, Tris-buffered saline ,tumorigenesis ,Endocrinology ,siRNA, small interfering RNA ,Cancer cell ,Cancer research ,LLC, Lewis lung carcinoma ,FCS, fetal calf serum ,Carcinogenesis ,knockout mouse - Abstract
mPGES-1 (microsomal prostaglandin E synthase-1) is a stimulus-inducible enzyme that functions downstream of COX (cyclo-oxygenase)-2 in the PGE2 (prostaglandin E2)-biosynthesis pathway. Although COX-2-derived PGE2 is known to play a role in the development of various tumours, the involvement of mPGES-1 in carcinogenesis has not yet been fully understood. In the present study, we used LLC (Lewis lung carcinoma) cells with mPGES-1 knockdown or overexpression, as well as mPGES-1-deficient mice to examine the roles of cancer cell- and host-associated mPGES-1 in the processes of tumorigenesis in vitro and in vivo. We found that siRNA (small interfering RNA) silencing of mPGES-1 in LLC cells decreased PGE2 synthesis markedly, accompanied by reduced cell proliferation, attenuated Matrigel™ invasiveness and increased extracellular matrix adhesion. Conversely, mPGES-1-overexpressing LLC cells showed increased proliferating and invasive capacities. When implanted subcutaneously into wild-type mice, mPGES-1-silenced cells formed smaller xenograft tumours than did control cells. Furthermore, LLC tumours grafted subcutaneously into mPGES-1-knockout mice grew more slowly than did those grafted into littermate wild-type mice, with concomitant decreases in the density of microvascular networks, the expression of pro-angiogenic vascular endothelial growth factor, and the activity of matrix metalloproteinase-2. Lung metastasis of intravenously injected LLC cells was also significantly less obvious in mPGES-1-null mice than in wild-type mice. Thus our present approaches provide unequivocal evidence for critical roles of the mPGES-1-dependent PGE2 biosynthetic pathway in both cancer cells and host microenvironments in tumour growth and metastasis.
- Published
- 2009