Par-4, a proapoptotic gene, is regulated by NSAIDs in human colon carcinoma cells.
OBJECTIVE
Many reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic effects, but the precise molecular mechanism(s) responsible are unclear. We evaluated the effect of cyclooxygenase (COX) inhibitors (NSAIDs) on human colon carcinoma cells (HCA-7) and identified several genes that are regulated after treatment with NS-398, a selective COX-2 inhibitor.


METHODS
Differential display polymerase chain reaction cloning techniques were used to identify genes regulated by treatment with NSAIDs and selective COX-2 inhibitors.


RESULTS
A prostate apoptosis response 4 (Par-4) gene was up-regulated after NSAID treatment. Par-4 was first isolated from prostate carcinoma cells undergoing apoptosis, and expression of Par-4 sensitized cancer cells to apoptotic stimuli. Par-4 levels were increased in cells treated with COX inhibitors such as NS-398, nimesulide, SC-58125, and sulindac sulfide. Treatment of HCA-7 cells with these agents also induced apoptotic cell death.


CONCLUSIONS
The results suggest that regulation of Par-4 contributes to the proapoptotic effects of high-dose COX inhibitors (NSAIDs) by serving as a downstream mediator leading to initiation of programmed cell death.
Zhang
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Division of Gastroenterology, Department of Medicine and Cell Biology, Vanderbilt University Medical Center, Veterans Affairs Medical Center, Nashville, Tennessee, USA.
DuBois
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D003110:Colonic Neoplasms; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D009578:Nitrobenzenes / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D016861:Cyclooxygenase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009578:Nitrobenzenes; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C101296:prostate apoptosis response-4 protein; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D013467:Sulindac; C025462:sulindac sulfide; D011493:Protein Kinase C; C012655:nimesulide