Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398.
We determined the effect of the highly selective cyclooxygenase-2 (COX-2) inhibitor NS-398 on proliferation, apoptosis and COX-2 regulation in 3 pre-malignant human colorectal adenoma cell lines (RG/C2, AA/C1, RR/C1) and compared its effect on 3 colorectal carcinoma cell lines (HT29, KS, JW2). COX-2 protein was expressed in each cell line derived from an adenoma, thus providing evidence that COX-2 is expressed in the tumour cells themselves at an early stage in human colorectal adenoma formation. NS-398 (20 to 100 microM for 96 h) induced apoptosis and inhibited the proliferation of the adenoma cell lines. Of the 3 carcinoma lines, only HT29 expressed COX-2 protein, yet each line was similarly sensitive to NS-398. There was a positive correlation between overall sensitivity of the cell lines (determined by the attached cell yield) and sensitivity to NS-398-induced apoptosis, suggesting that apoptosis is the dominant anti-proliferative effect of NS-398. Two of the 3 adenoma cell lines (RG/C2, AA/C1) were less sensitive than the carcinoma cell lines. NS-398 up-regulated COX-2 protein expression in the HT29 and adenoma cell lines. This was studied further in HT29 cultures, where treatment with NS-398 inhibited COX-2 activity, reducing prostaglandin E(2) secretion. Here, neither the increase in COX-2 protein expression nor the anti-proliferative and apoptosis-inducing effect of NS-398 was prevented by addition of exogenous prostaglandin E(2). Apoptosis appears to be the dominant anti-proliferative effect of NS-398 and, in COX-2 expressing cells, may be mechanistically linked to the observed induction of COX-2 protein expression upon treatment with NS-398.
Elder
D J
DJ
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, UK. Douglas.Elder@bristol.ac.uk
Halton
D E
DE
Crew
T E
TE
Paraskeva
C
C
D000236:Adenoma / Q000201:enzymology / Q000473:pathology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011459:Prostaglandins E, Synthetic; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C017244:16,16-dimethylprostaglandin E; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases