Antisense Inhibition of the p65 Subunit of NF-κB Blocks Tumorigenicity and Causes Tumor Regression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 21; pp. 9901 - 9905
• Main Authors: Higgins, Kimberly A., Perez, Jose R., Coleman, Timothy A., Dorshkind, Kenneth, McComas, Warren A., Sarmiento, Ulla M., Rosen, Craig A., Narayanan, Ramaswamy
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.11.1993; National Acad Sciences
• Subjects: 3T3 cells; Animals; Antineoplastic agents; Antisense oligonucleotides; Antisense RNA; Biological and medical sciences; Cell adhesion; Cell Division - drug effects; Cell growth; Cell Line; Cell lines; Cell Transformation, Neoplastic; Dexamethasone - pharmacology; Fibrosarcoma - pathology; General aspects; Humans; Macromolecular Substances; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; NF-kappa B - biosynthesis; NF-kappa B - genetics; Oligonucleotides; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; RNA, Antisense - biosynthesis; RNA, Antisense - metabolism; Thionucleotides; Transformed cell line; Tumor cell line; Tumor Cells, Cultured; Tumors; Antineoplastic agent; Animal model; Rodentia; Cytotoxicity; Fibrosarcoma; Antisense RNA; Malignant tumor; Subunit; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Cell line; Treatment; Mouse; Transcription factor NFκB; Mechanism of action; Tumor cell
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.21.9901

The NF-κB 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-κB binding sites and may play an important role in inflammatory response, tumorigenicity, and metastasis. In an earlier study, we demonstrated that adhesion of diverse transformed cells was blocked by antisense inhibition of the p65 subunit of NF-κB. Since cell-substratum interactions play an important role in tumorigenicity, we reasoned that antisense p65 could inhibit tumorigenicity. In diverse transformed cell lines, phosphorothioate antisense oligonucleotides to p65 inhibited in vitro growth, reduced soft-agar colony formation, and eliminated the ability of cells to adhere to an extracellular matrix. Stable transfectants of a fibrosarcoma cell line expressing dexamethasone-inducible antisense RNA to p65 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. The administration of antisense but not sense p65 oligonucleotides caused a pronounced inhibition of tumorigenicity in nude mice injected with diverse tumor-derived cell lines. Inhibitors of NF-κB function may thus be useful in the treatment of cancer.