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Par-4, a proapoptotic gene, is regulated by NSAIDs in human colon carcinoma cells
1Division of Gastroenterology, Department of Medicine and Cell Biology, Vanderbilt University Medical Center, Veterans Affairs Medical Center, Nashville, Tennessee, USA.
Background & Aims:
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.
Insights
Nonsteroidal anti-inflammatory drugs (NSAIDs) increase prostate apoptosis response 4 (Par-4) gene expression. This regulation contributes to the cancer-fighting effects of NSAIDs by initiating programmed cell death in colon cancer cells.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are reported to possess antineoplastic effects.
- The precise molecular mechanisms underlying NSAIDs' anti-cancer activity remain largely unelucidated.
- Cyclooxygenase (COX) inhibitors, a class of NSAIDs, are investigated for their role in cancer treatment.
Purpose of the Study:
- To evaluate the effects of cyclooxygenase (COX) inhibitors on human colon carcinoma cells (HCA-7).
- To identify specific genes regulated by treatment with selective COX-2 inhibitors, such as NS-398.
- To elucidate the molecular pathways involved in NSAID-induced apoptosis in cancer cells.
Main Methods:
- Differential display polymerase chain reaction (DD-PCR) cloning techniques were employed.
- Gene expression profiles were analyzed following treatment with NSAIDs and selective COX-2 inhibitors.
- Human colon carcinoma-7 (HCA-7) cells were utilized as the experimental model.
Main Results:
- Prostate apoptosis response 4 (Par-4) gene was identified as significantly up-regulated after NSAID treatment.
- Increased Par-4 levels were observed in HCA-7 cells treated with various COX inhibitors, including NS-398, nimesulide, SC-58125, and sulindac sulfide.
- Treatment with these COX inhibitors induced apoptotic cell death in HCA-7 cells.
Conclusions:
- The study suggests that Par-4 gene regulation is a key component of the proapoptotic effects of high-dose COX inhibitors.
- Par-4 acts as a downstream mediator, initiating programmed cell death in response to NSAID treatment.
- These findings highlight a potential molecular mechanism for the anti-cancer properties of NSAIDs.