Aspirin induces apoptosis through the inhibition of proteasome function.
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.
Dikshit
Priyanka
P
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122050, India.
Chatterjee
Mou
M
Goswami
Anand
A
Mishra
Amit
A
Jana
Nihar Ranjan
NR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology*; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D061988:Proteasome Inhibitors; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex; D001241:Aspirin