科研之友
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摘要
Colorectal cancer (CRC) is the most common gastrointestinal malignancy. Most of the clinical data on CRC prevention have come from the use of aspirin. Besides inhibition of cyclooxygenases, aspirin has a diversity of molecular effects that counteract colon carcinogenesis. Aspirin restrains cell proliferation by inducing a G(1) arrest in colorectal cells. To determine which cell cycle checkpoint pathways are involved in this response, colorectal cell lines wild-type or defective for p53 and p21(Waf1)/(Cip1) were treated with aspirin or the anti-proliferative drug sulindac sulfide, then assayed for proliferative activity, for cell cycle progression and apoptosis, for the activation and phosphorylation of checkpoint components and for the transcriptional up-regulation of p21(Waf1/Cip1) and Bax. Aspirin and sulindac sulfide induced a G(1) arrest within 48 h. While all cell lines responded in a comparable way to sulindac sulfide, the aspirin-induced G(1) arrest was dependent on p21(Waf1/Cip1) - as cells lacking the cyclin-dependent kinase inhibitor failed to show this arrest - and on ataxia-telangiectasiamutated kinase (ATM) - as the inhibitor caffeine abrogated the checkpoint. Moreover, aspirin induced cell death mainly in cells expressing p53. Aspirin induced the phosphorylation of p53 at residue Ser15 within 8 h in a caffeine-dependent manner, and also caused the activation of checkpoint kinase 2 and the cleavage of caspase 7. Our results suggest that aspirin induces a G(1) arrest and apoptosis by activating p53 and p21(Waf1/Cip1) in an ATM-dependent way. By activating these checkpoint pathways, aspirin may restrain uncontrolled proliferation of colorectal cells, enhance their response to stresses such as DNA damage and promote entry of abnormal cells into apoptosis.
- 出版日期2007-10
