Aspirin Induces Apoptosis through the Inhibition of Proteasome Function

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, IB-␣, p53, and p27 kip1 . Aspirin-induced proteasomal malfunction might be responsible, at least in part, for the downregulation 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.

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

“…53,54,59 Recent studies have shown that MCF-7 mammospheres are insensitive to the cyclooxygenase pathway, and the COX-2 inhibitor (Indomethacin) was unable to reduce the mammosphere-forming capacity of MDA-MB-231 cells. However, these studies also showed that prostaglandin E receptor, which is a downstream regulator of COX-2 enzyme, plays critical role in regulation of stemness of BC cells.…”

Aspirin reduces the apoptotic effect of etoposide via Akt activation and up-regulation of p21cip

“…Aspirin has multiple COX-independent effects and is involved in various cellular processes such as apoptosis (10,12). On one hand, aspirin induces cell apoptosis via diverse pathways.…”

“…In vitro and animal studies have demonstrated that aspirin can induce cell apoptosis through COX-dependent and COX-independent pathways. The COX-independent effects include alteration of gene transcription (8,9), inhibition of proteasome function (10), cell cycle arrest, modulation of several protein kinases and other molecular signaling pathways (11,12) and down-regulation of nuclear factor-κB (NF-κB) activity by preventing phosphorylation and degradation of the inhibitory subunit IκB (13,14). All of these effects of aspirin are mainly observed in colon, breast and lung cancer.…”

Inhibitors of NF-κB signaling: 785 and counting

“…Aspirin is commonly thought to act pharmacologically primarily via inhibition of prostaglandin synthesis (Weissmann, 1991). However, at higher concentrations, aspirin has also been shown to block NF-kB activity by directly binding to and inhibiting the kinase activity of IKKb by reducing its ability to bind ATP (Yin et al, 1998); more recently, aspirin has also been reported to inhibit proteasome activity and consequently to interfere with degradation of IkB (Dikshit et al, 2006). As such, high-dose aspirin therapy may have applications to diseases where NF-kB activity is involved, including cancer (McCarty and Block, 2006), diabetes (Yuan et al, 2001) and heart disease (Li and Fang, 2004).…”