Abstract
Aspirin and other nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and prevention of carcinogenesis. However, the molecular mechanisms through which these compounds induce apoptosis are not well understood. Here we have found that aspirin treatment of the mouse Neuro 2a cells impaired the proteasome function and caused severe mitochondrial abnormalities. Treatment with aspirin lead to a dose- and time-dependent decrease in proteasome activity and an increase in the accumulation of ubiquitylated proteins in the cells, which correlated with its effect on cell death. Aspirin exposure also resulted in an increase in the half-life of pd1EGFP, a model substrate of proteasome, as well as various intracellular substrates like Bax, IkappaB-alpha, p53, and p27(kip1). Aspirin-induced proteasomal malfunction might be responsible, at least in part, for the down-regulation of NF-kappaB activity and neurite outgrowth. Finally, we have shown that aspirin treatment caused changes in the mitochondrial membrane potential, release of cytochrome c from mitochondria, and activation of caspase-9 and -3, which could be because of the proteasomal dysfunction.
Highlights
The cells were plated onto 96-well tissue culture plates, and on the following day, the cells were exposed to the different doses of aspirin for 24 h
Because the caspase-9 activation is initiated with the release of cytochrome c from mitochondria followed by binding to apoptosis protease-activating factor-1, we further examined the activation of caspase-9 and subsequent events upon aspirin treatment
We report that aspirin inhibits the proteasome function and causes severe mitochondrial abnormalities
Summary
Aspirin and other nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and prevention of carcinogenesis. Aspirin has been found to induce both the extrinsic (the death receptor) and intrinsic (the mitochondrial) pathway of caspase activation [10, 12, 14], but how it does so is not well understood. The pharmacological inhibition of proteasome function has been found to induce the dual apoptotic signaling pathways, depending on the cell types and conditions (26 –32). We demonstrate that aspirin inhibits the proteasome function, induces mitochondrial abnormalities, and activates intrinsic pathway of apoptosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
