ANTISENSE INHIBITION OF THE P65 SUBUNIT OF NF-KAPPA-B BLOCKS TUMORIGENICITY AND CAUSES TUMOR-REGRESSION

The NF-kappaB transcription factor, composed of two proteins, p50 and p65, is a pleiotropic activator that participates in the induction of a wide variety of cellular genes. Various cell adhesion molecules have NF-kappaB binding sites and may play an important role in inflammator y response, tumorigenicity, and metastasis. In an earlier study, we de monstrated that adhesion of diverse transformed cells was blocked by a ntisense inhibition of the p65 subunit of NF-kappaB. Since cell-substr atum interactions play an important role in tumorigenicity, we reasone d that antisense p65 could inhibit tumorigenicity. In diverse transfor med cell lines, phosphorothioate antisense oligonucleotides to p65 inh ibited in vitro growth, reduced soft-agar colony formation, and elimin ated the ability of cells to adhere to an extracellular matrix. Stable transfectants of a fibrosarcoma cell line ''pressing dexamethasone-in ducible antisense RNA to p65 showed inhibition of in vitro growth and in vivo tumor development. In response to inducible expression of anti sense RNA, a pronounced tumor regression was seen in nude mice. The ad ministration of antisense but not sense p65 oligonucleotides caused a pronounced inhibition of tumorigenicity in nude mice injected with div erse tumor-derived cell lines. Inhibitors of NF-kappaB function may th us be useful in the treatment of cancer.