A Twenty-First Century Cancer Epidemic Caused by Obesity: The Involvement of Insulin, Diabetes, and Insulin-Like Growth Factors
Figure 9
Therapeutic strategies to inhibit insulin, IGF-1, and IGF-2 signal transduction. Graphic representations of the insulin receptor isoform B (IR-B, dark blue), the insulin receptor isoform A (IR-A, lighter blue), and of the type I IGF receptor (IGF-IR, pink) are shown as homodimeric or heterodimeric hybrid receptors. For each receptor monomer, the α-chain is coloured slightly lighter than the β-chain. Bars indicate the approximate positions of the single disulphide bonds between the C647 in the α-chain and C860 in the β-chain of each receptor monomer (yellow); the single disulphide bond between the FnIII-1 domains of each of the two α chains in each dimer is obscured. The extracellular ligands, insulin (orange), IGF-2 (ochre), and IGF-1 (pale yellow), are shown as triangles. The downward pointing grey arrows indicate that a signal has been transduced from a receptor dimer (a). The deep yellow spheres attached to the ectodomains of the activated receptors represent phosphorylated residues. Antibodies against IGF-1 and IGF-2 (IGF mAb; yellow), and recombinant insulin-like binding protein as an incomplete sphere (rIGFBP; light blue), are shown. Inhibition of a signal transduction molecule that is affected by one of the inhibitors is indicated by an inhibition symbol (brick red). Absence of a signal from a receptor dimer is indicated by a red cross below the receptor dimer (b). Monoclonal antibodies against IGF-1 and IGF-2 will not inhibit insulin signal transduction. Recombinant IGFBP will inhibit IGF-1 and IGF-2 but will not inhibit insulin. Antibodies specific for type I IGF receptor are shown (Type I IGF receptor mAb; deep pink) (c). Antibodies specific for the type I IGF receptor will inhibit type I IGF receptor homodimer and its hybrid receptors formed with both isoforms of the insulin receptor but will not inhibit insulin receptor homodimers or hybrids of the two isoforms of the insulin receptor. Representations of tyrosine kinase inhibitors (TKIs) that inhibit both the insulin and type I IGF receptors (tyrosine kinase inhibitor; violet) are illustrated (d). Tyrosine kinase inhibitors that affect type I IGF receptor and the insulin receptor will inhibit signal transduction via all the insulin and IGF signal transduction pathways. Tyrosine kinase inhibitors that are specific for the type I IGF receptor will inhibit the type I IGF receptor homodimer and its hybrid receptors but will not inhibit insulin receptor homodimers or hybrids of the two isoforms.
