Rat glioblastoma cells expressing an antisense RNA to the insulin-like growth factor-1 (IGF-1) receptor are nontumorigenic and induce regression of wild-type tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 1994-04, Vol.54 (8), p.2218-2222
• Main Authors: RESNICOFF, M, SELL, C, RUBINI, M, COPPOLA, D, AMBROSE, D, BASERGA, R, RUBIN, R
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Base Sequence; Biological and medical sciences; Cell Adhesion; Cell Division - drug effects; Cell Line; General aspects; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Insulin-Like Growth Factor I - metabolism; Kinetics; Medical sciences; Molecular Sequence Data; Oligodeoxyribonucleotides - pharmacology; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; Rats; Receptor, IGF Type 1 - biosynthesis; Receptor, IGF Type 1 - genetics; Recombinant Proteins - metabolism; RNA, Antisense - biosynthesis; Transfection; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445

Insulin-like growth factor-1 (IGF-1) and IGF-2 are critical regulators of cell proliferation. The growth-promoting action of both ligands is mediated by the type 1 IGF receptor (IGF-1R). We have investigated the role of the IGF-1R in the growth and tumorigenicity of rat C6 glioblastoma cells. For this purpose, antisense RNA to IGF-1R RNA was introduced into cells by either the addition of oligodeoxynucleotides or by transfection with plasmids that express antisense RNA to IGF-1R RNA. At low cell density, C6 cells grew slowly in serum-free medium and proliferated with the sole addition of IGF-1 or IGF-2. Both antisense IGF-1R oligodeoxynucleotides and stable transfection with a plasmid expressing an antisense IGF-1R RNA inhibited IGF-1-mediated growth in monolayers and clonogenicity in soft agar. Sense oligodeoxynucleotides and sense-expressing plasmid had no effect on either parameter. In stable antisense transfectants, tyrosine-phosphorylated IGF-1 receptors were not detectable, although they were easily detected in wild-type cells. When wild-type C6 cells were injected s.c. into syngeneic immunocompetent rats, tumors developed within 1 week. In contrast, stably transfected C6 cells overexpressing antisense IGF-1R RNA were nontumorigenic. Moreover, when C6 IGF-1R antisense cells were injected, subsequent tumor formation by wild-type C6 cells was completely prevented. Finally, injection of C6 IGF-1R antisense cells into rats carrying an established wild-type C6 tumor caused complete regression of the tumors. The results demonstrate the critical importance of the IGF-1R in glioblastoma cell growth, clonogenicity, and tumorigenicity. Although the mechanism is presently unknown, the fact that the injection of C6 cells expressing an antisense RNA to IGF-1R RNA leads to regression of already established wild-type C6 tumors suggests the possibility of practical applications.