Insulin receptor and cancer

Abstract

The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

“…Insulin, a key mediator of important metabolic functions, coordinates and regulates the storage and release of the body's fuel (Belfiore & Malaguarnera 2011). Insulin, which is secreted by b-cells of the pancreas in response to increasing blood glucose levels, binds to the cognate receptor (INSR) mainly expressed by hepatocytes, adipocytes, and muscle cells as well as prostate and breast tissues (Belfiore & Malaguarnera 2011).…”

“…Insulin, which is secreted by b-cells of the pancreas in response to increasing blood glucose levels, binds to the cognate receptor (INSR) mainly expressed by hepatocytes, adipocytes, and muscle cells as well as prostate and breast tissues (Belfiore & Malaguarnera 2011). So far, two INSR isoforms have been identified, isoform A (INSR-A) and isoform B (INSR-B), which are usually co-expressed and regulated by several factors (Belfiore 2007).…”

“…Expression of INSR-A has been predominantly detected in fetal tissues and tumors as found in leiomyosarcoma cells (Vigneri et al 2009, Morcavallo et al 2011. Aside from its important contribution to maintenance of metabolic activity and glucose homeostasis, insulin shows mitogenic potential which can lead to an increased risk of certain types of cancer (Belfiore & Malaguarnera 2011). Accordingly, it has been suggested that direct INSR stimulation activates diverse transduction mechanisms involved in tumor development (Belfiore & Malaguarnera 2011).…”

“…Aside from its important contribution to maintenance of metabolic activity and glucose homeostasis, insulin shows mitogenic potential which can lead to an increased risk of certain types of cancer (Belfiore & Malaguarnera 2011). Accordingly, it has been suggested that direct INSR stimulation activates diverse transduction mechanisms involved in tumor development (Belfiore & Malaguarnera 2011). Moreover, in cancer patients affected by insulin resistance, increased insulin levels combine with frequent INSR overexpression in tumor cells, leading to abnormal stimulation of nonmetabolic effects mediated by INSR, such as cell survival, proliferation, and migration (Belfiore & Malaguarnera 2011).…”

Association between serum levels of insulin‐like growth factor‐1, bioavailable testosterone, and pathologic Gleason score

“…Of these, IGF‐1 mainly originates in the liver and shows low inter‐individual variability in its circulating levels 4. Binding of ligand to the IGF‐1 receptor (IGF1R) leads to the phosphorylation of Src homology 2 domain‐containing (SHC)‐transforming protein and subsequent activation of the Ras pathway, and phosphorylation of insulin receptor substrate (IRS)‐1 protein, which induces the activation of the phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathway 5. The relationship between serum IGF‐1 level and prostate cancer is of interest because previous studies have suggested that aspects of energy metabolism and balance are associated with the incidence of prostate cancer,6 and the effect of environmental factors on prostate cancer risk may be mediated by differences in the concentrations of substances including testosterone and prostate‐specific antigen (PSA) 7…”