Annexin 1 induced by anti-inflammatory drugs binds to NF-kappaB and inhibits its activation: anticancer effects in vitro and in vivo.
Annexin A1 (ANXA1), a mediator of the anti-inflammatory action of glucocorticoids, is important in cancer development and progression, whereas NF-kappaB 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-kappaB and suppressed its transcriptional activity by preventing NF-kappaB binding to DNA. The induction of ANXA1 by glucocorticoids was proportional to their anti-inflammatory potency, as was the suppression of NF-kappaB activity, which was accompanied by enhanced apoptosis and inhibition of cell growth mediated by changes in NF-kappaB-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-kappaB. 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-kappaB 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.
Zhang
Zhiquan
Z
Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8173, USA.
Huang
Liqun
L
Zhao
Wenping
W
Rigas
Basil
B
D000818:Animals; D017305:Annexin A1 / Q000096:biosynthesis / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D017305:Annexin A1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D016328:NF-kappa B; D051996:Transcription Factor RelA; C098312:nitroxy-butyl-acetylsalicylic acid; D003907:Dexamethasone; D001241:Aspirin