Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells.
BACKGROUND
Cyclooxygenase-2 (COX-2) over-expression and subsequent prostaglandin E2 (PGE2) production are frequently associated with human non-small-cell lung cancer (NSCLC) and are involved in tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that ciglitazone downregulates PGE2 in NSCLC cells.


METHODS
PGE2 ELISA assay and COX-2 ELISA assay were performed for measuring PGE2 and COX-2, respectively, in NSCLC. The mRNA level of COX-2 was measured by semi-quantitative RT-PCR. The transient transfection experiments were performed to measure COX-2 and peroxisome proliferator-response element (PPRE) promoter activity in NSCLC. Western blots were unitized to measure PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein expression.


RESULTS
COX-2 ELISA assays suggested that ciglitazone-dependent inhibition of PGE2 occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 mRNA expression and COX-2 promoter activity while upregulating PPRE promoter activity. Ciglitazone did not modify the expression of enzymes downstream of COX-2 including PGES and 15-PGDH. Utilization of a dominant-negative PPARgamma showed that the suppression of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways.


CONCLUSIONS
Taken together, our findings suggest that ciglitazone is a negative modulator of COX-2/PGE2 in NSCLC.
Hazra
Saswati
S
Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Shazra@mednet.ucla.edu
Dubinett
Steven M
SM
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*
D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; C039671:ciglitazone
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