Annexin 1 Induced by Anti-Inflammatory Drugs Binds to NF-κB and Inhibits Its Activation: Anticancer Effects In vitro and In vivo

Abstract

Annexin A1 (ANXA1), a mediator of the anti-inflammatory action of glucocorticoids, is important in cancer development and progression, whereas NF-κB regulates multiple cellular phenomena, some of them associated with inflammation and cancer. We showed that glucocorticoids and chemopreventive modified nonsteroidal anti-inflammatory drugs, such as nitric oxide-donating aspirin (NO-ASA) and phospho-aspirin, induced ANXA1 in cultured human colon and pancreatic cancer cells. ANXA1 associated with NF-κB and suppressed its transcriptional activity by preventing NF-κB binding to DNA. The induction of ANXA1 by glucocorticoids was proportional to their anti-inflammatory potency, as was the suppression of NF-κB activity, which was accompanied by enhanced apoptosis and inhibition of cell growth mediated by changes in NF-κB-dependent cell signaling. The proposed novel mechanism was operational in the intestinal mucosa of mice treated with dexamethasone or NO-ASA. ANXA1-based oligopeptides displayed the same effects as ANXA1 on NF-κB. One such tripeptide (Gln-Ala-Trp) administered to nude mice inhibited the growth of SW480 human colon cancer xenografts by 58% compared with control (P < 0.01). Our findings reveal that ANXA1 is an inducible endogenous inhibitor of NF-κB in human cancer cells and mice, provide a novel molecular mechanism for the action of anti-inflammatory agents, and suggest the possibility of mechanism-driven drug development.

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…Acetylation of COX-2 by glucocorticoid and aspirin can trigger 15-epi-LXA 4 biosynthesis (Perretti et al, 2002a). Intriguingly, glucocorticoid and non-steroidal antiinflammatory drugs have provided potential treatments for cancer (Coimbra et al, 2009;Zhang et al, 2010b). Hence, ANXA1 and LXs may be involved in the anti-inflammation and anticancer role as COXs inhibitors.…”

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

“…These findings and the demonstration that silencing ANXA1 attenuates activation of NF-kB indicates that ANXA1 can regulate the transcriptional function of NF-kB-p65. Zhang et al (2010) reported that ANXA1 is induced by anti-inflammatory drugs and can associate with NF-kB-p65 and this complex negatively regulates NF-kB in colon and pancreatic cancer cells. We show in our study that ANXA1 is a positive regulator of NF-kB activity, and interacts with NF-kB-p65, as well as other upstream components of the NF-kB pathway.…”

Molecular regulators of resolution of inflammation: potential therapeutic targets in the reproductive system

“…Recent data also shows that GC induction of ANXA1 in cancer cells is correlated with the order of antiinflammatory potency of the respective GCs (Zhang et al 2010). GC stimulation of macrophages in vitro stimulates both release of existing stores of ANXA1 and de novo synthesis, with correspondingly biphasic kinetics (Flower 1988), while neutrophil ANXA1 levels are correlated with serum cortisol, suggesting GC regulation in vivo (Mulla et al 2005).…”