The NF-kappaB transcription factor in oncogenesis.
The NF-kappaB transcription factor complex is a pleiotropic activator that participates in the induction of a wide variety of cellular and viral genes. The active complex is composed of two subunits designated NFKB1 and RelA (formerly called p50 and p65, respectively). Binding sites for NF-kappaB are present in the promoter region of many cell adhesion molecules, cytokines and growth factors. Antisense inhibition of the individual subunits of NF-kappaB exerted differential effects on cell adhesion. Antisense phosphorothioate oligomers to relA but not NFKB1 caused a rapid inhibition of cell adhesion in diverse cell types. Antisense relA oligomers exerted antigrowth effects on diverse transformed cells in vitro and caused a pronounced inhibition of tumorigenicity in nude mice tumor models. Stable transfectants of a fibrosarcoma cell line expressing dexamethasone-inducible antisense RNA to relA also showed inhibition of in vitro growth and in vivo tumor development. In response to inducible expression of antisense RNA, a pronounced tumor regression was seen in nude mice. Use of a "decoy" approach to inhibit RelA function directly also caused inhibition of tumor cell growth in vitro and in vivo. Our results indicate that key regulatory molecules such as transcription factors can be selectively targeted for therapeutic intervention in cancer.
Sharma
H W
HW
Division of Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA.
Narayanan
R
R
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002448:Cell Adhesion / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism
D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors