A Soluble Insulin-like Growth Factor I Receptor That Induces Apoptosis of Tumor Cells in Vivo and Inhibits Tumorigenesis

By a frame-shift mutation, we have engineered a human IGF-I receptor (IGF-IR) cDNA that produces a receptor 486 amino acids long (plus the 30 amino acids of the signal peptide). This receptor, which we have designated as 486/STOP, is partially secreted into the medium of cells in culture and markedly inhibits the autophosphorylation of the endogenous IGF-IRs as well as the activation of the signaling pathway. The 486/STOP receptor acts as a strong dominant negative for several growth functions: ( a ) it inhibits the growth of cells in monolayers; ( b ) it inhibits the growth of transformed cells in soft agar; ( c ) it induces extensive apoptosis in vivo ; and ( d ) it inhibits tumorigenesis in syngeneic rats. This is the first demonstration that a dominant negative of the IGF-IR can induce massive apoptosis of tumor cells in vivo .