Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer.
An inducible microsomal form of human prostaglandin E synthase (mPGES) was recently identified. This enzyme converts the cyclooxygenase (COX) product, prostaglandin (PG) H2, to PGE2, a prostanoid that has been implicated in carcinogenesis. Increased amounts of PGE2 are detected in many types of cancer, but the underlying mechanism is not fully understood. Hence, we compared amounts of mPGES in 19 paired samples (tumor and adjacent normal tissue) of non-small cell lung cancer (NSCLC). By immunoblot analysis, mPGES was overexpressed in about 80% of NSCLCs. Immunohistochemistry localized the expression of mPGES to neoplastic epithelial cells. COX-2 was also commonly up-regulated in these tumors; marked differences in the extent of up-regulation of mPGES and COX-2 were observed in individual tumors. Cell culture was used to define the underlying mechanism(s) that accounts for up-regulation of mPGES in NSCLC. As reported previously for COX-2, levels of mPGES mRNA and protein were increased in NSCLC cell lines containing mutant Ras as compared with a nontumorigenic bronchial epithelial cell line. Nuclear run-offs revealed increased rates of mPGES transcription in the transformed cell lines. Overexpression of Ras caused a severalfold increase in mPGES promoter activity in nontransformed cells. Tumor necrosis factor-alpha induced mPGES and COX-2 in NSCLC cell lines but had no effect on the expression of either enzyme in a nontumorigenic bronchial epithelial cell line. Consistent with prior observations for COX-2, these data suggest that both cellular transformation and cytokines contribute to the up-regulation of mPGES in NSCLC.
Yoshimatsu
K
K
Department of Medicine, Weill Medical College of Cornell University and Strang Cancer Prevention Center, New York, New York 10021, USA.
Altorki
N K
NK
Golijanin
D
D
Zhang
F
F
Jakobsson
P J
PJ
Dannenberg
A J
AJ
Subbaramaiah
K
K
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D019746:Intramolecular Oxidoreductases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases