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J. Biol. Chem., Vol. 281, Issue 39, 29228-29235, September 29, 2006

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Aspirin Induces Apoptosis through the Inhibition of Proteasome Function^*

From the Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122050, India

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, IB-, p53, and p27^kip1. Aspirin-induced proteasomal malfunction might be responsible, at least in part, for the down-regulation of NF-B 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.

Received for publication, March 21, 2006

^* This work was supported by a grant from the Department of Biotechnology, Government of India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a research fellowship from the Council of Scientific and Industrial Research, Government of India.

² To whom correspondence should be addressed. Tel.: 91-124-2338922; Fax: 91-124-2338910; E-mail: nihar{at}nbrc.ac.in.

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