The Pathway from Diabetes and Obesity to Cancer, on the Route to Targeted Therapy

On the Route to Targeted Therapy

Emily J. Gallagher, MBBCh, MRCPI; Yvonne Fierz, MD; Rosalyn D. Ferguson, PhD; Derek LeRoith, MD, PhD

Disclosures

Endocr Pract. 2010;16(5):864-873. 

In This Article

Insulin and IGF-1 Signaling

Insulin and IGF-1 Receptors

Insulin is produced mainly by the pancreatic β cells, while IGF-1 is synthesized largely in the liver in response to the action of growth hormone on the growth hormone receptor. Insulin increases the expression of growth hormone receptors and enhances postreceptor signaling; therefore, hyperinsulinemia may lead to increased production of IGF-1.[29]

Insulin signals primarily through the insulin receptor, while IGF-1 signals primarily through the IGF-1 receptor. Insulin receptor signaling mainly mediates metabolic effects, while IGF-1 receptor signaling leads to growth and proliferation. The insulin receptor and IGF-1 receptor have a similar structure, with an α and β subunit joined to another α and β subunit by disulfide bonds. The insulin receptor has 2 isoforms formed by alternative splicing of exon 11: insulin receptor-A lacks exon 11, while exon 11 is present in insulin receptor-B. Cells that express both the insulin receptor and IGF-1 receptor can also express hybrid receptors, consisting of an α and β subunit from an insulin receptor bound to an α and β subunit of an IGF-1 receptor (Fig. 2).[30]

Figure 2.

The insulin receptors (IR-A and IR-B), the insulinlike growth factor 1 receptor (IGF-1R), and the hybrid receptors (IGF-1R/IR-A and IGF-1R/IR-B). Insulin signals primarily through IR-A and IR-B with lower affinity for IGF-1R. IGF-1 binds to the IGF-1R and IGF-1R/IR-A and IGF-1R/IR-B hybrids. IGF-2 binds to the IR-A, IGF-1, and IGF-1R/IR-A hybrid receptor. Binding of insulin and IGF-2 to the IR-A by insulin predominantly results in mitogenic signaling. Activation of the IR-B receptor initiates metabolic signaling. IGF-1 and IGF-2 signaling through the IGF-1R mostly activates mitogenic signaling pathway, as does binding to the IGF-1R/IR-A hybrid. Activation of the IGF-1R/IR-B hybrid leads to more metabolic effects.

Insulin has a high affinity for the insulin receptor-A and insulin receptor-B and a low affinity for the IGF-1 receptor, and it has no important binding with the hybrid receptors. IGF-1 can bind the IGF-1 receptor in addition to the hybrid receptors. IGF-2 preferentially binds the insulin receptor-A, IGF-1 receptor and IGF-1/insulin receptor-A hybrid (Fig. 2). Binding of insulin to insulin receptor-A leads to different signaling activation compared with IGF-2 binding. Insulin receptor-A is expressed in fetal tissue and tumor cells.[31] IGF-2 can also bind to the IGF-2 receptor, leading to endocytosis and clearance of IGF-2 from the circulation.[30]

Tumor cells expressing greater quantities of insulin receptor-A, IGF-1 receptor, or hybrid receptors will allow for increased activation of mitogenic signaling pathways, particularly in the presence of increased levels of insulin, IGF-1, or IGF-2.

Insulin and IGF Signaling

Binding of insulin to the insulin receptor and IGF-1 or IGF-2 to the IGF-1 receptor leads to autophosphorylation of the β subunit of the receptors and the exposure of phosphorylated residues that function as docking sites for IRS and adaptor proteins (Shc, Gab1, APS). Phosphorylation of IRS-1 leads to activation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K); activation of the PI3K pathway results in activation of protein kinase B (Akt). Akt inhibits apoptosis and stimulates protein synthesis, as shown in Figure 3. Protein synthesis is required for cells to grow and form the machinery necessary for cell cycle progression. It is regulated by signaling through the mammalian target of rapamycin (mTOR) (Fig. 3).[30,32–34] The MAPK pathway is activated by autophosphorylation of the IGF-1 receptor and recruitment of the adaptor protein Shc, leading to recruitment of Grb2 (growth factor receptor bound protein 2). This results in the recruitment and activation of Ras and activation of the Raf-1/MEK/ERK pathway, eventually leading to cellular proliferation.[30,33] IGF-1 receptor signaling can also phosphorylate the Janus kinases (JAK-1 and JAK-2) involved in cytokine signaling. Phosphorylation of the JAK proteins can activate the signal transducers and activators of transcription (STAT) proteins leading to gene transcription. Activation of signal transducer and activator of transcription 3 (STAT3) may be responsible for the transforming activity of the IGF-1 receptor.[30] The cytokine signaling pathway feeds back to inhibit IGF-1 receptor signaling (Fig. 3).[33]

Figure 3.

Insulinlike growth factor 1 receptor (IGF-1R) signaling pathway. IGF-1 and IGF-2 bind to the α subunit of the IGF-1R. This results in phosphorylation of the insulin receptor substrate (IRS) with phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) and activation of the p110 catalytic subunit, resulting in the formation of phosphatidylinositol 3,4 phosphate (PIP2) and phosphatidylinositol 3,4,5 phosphate (PIP3). PIP3 then activates Akt. The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits PI3K. Akt inhibits apoptosis by inactivating BCL-2 antagonist of cell death (BAD) and stimulates protein synthesis by activating the mammalian target of rapamycin (mTOR). mTOR activates the ribosomal S6 kinase (S6K) and eukaryotic initiation factor 4E binding protein-1 (4E-BP-1), leading to protein synthesis. mTOR activation is inhibited by the tuberous sclerosis complex (TSC1/TSC2). In the absence of cellular nutrients, AMPK levels increase and inhibit protein synthesis through effects on TSC1/2 and mTOR. Signaling through the IGF-1R also activates the adaptor proteins Shc and Grb2, leading to activation of the mitogen-activated protein kinase (MAPK) pathway, which results in cell proliferation.

Understanding that insulin receptor signaling can promote protein synthesis and inhibit apoptosis and that IGF-1 receptor signaling enhances cell proliferation and transformation, allows us to understand that hyperinsulinemia and increased IGF-1 and IGF-2 concentrations may result in tumor growth. Points in these pathways, such as the insulin receptor, IGF-1 receptor, PI3K, Akt, and mTOR, are the targets of new antineoplastic pharmacologic agents.

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