Indian Journal of Biochemistry & Biophysics Vol. 51, December 2014, pp. 493-498 Review Insulin Signaling Network in Cancer Alpana Ray, Mohamed Alalem and Bimal K Ray* Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA Received 14 August 2014; revised 20 November 2014 The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states. Increased risk of developing a range of cancers is also seen with a certain treatment options used to lower blood glucose level in diabetic patients. While metformin monotherapy has the lowest risk of developing cancer, in comparison, treatment with insulin or insulin secretagogues shows more likelihood to develop solid cancers. Cellular signaling initiated by insulin provides a clue regarding these diverse cellular outcomes. This review discusses how the insulin enacts such diverse physiological effects and the insulin-cancer relationship, with focus on the role of insulin signaling in cancer. Keywords: Insulin, Insulin-like growth factors, Insulin receptors, IGF-R, Insulin-like growth factor receptor, Insulin receptor substrate, PI3 kinase, Akt, GLUT4, mTOR Introduction In the fall of 1921, Fredrick Banting and Charles Best discovered that extract prepared from pancreas can dramatically lower the high blood sugar level in depancreatized, diabetic dogs. Following this discovery, both Banting and Best along with James Collip, all working in the laboratory of John Macleod, purified an active ingredient called insulin. In early 1922, a human clinical trial of insulin on patients with diabetes mellitus showed great success. The discovery of insulin was announced on May 3, 1922 by Macleod at a meeting of the Association of American Physicians. For their pioneering work on insulin, Banting and Macleod received the 1923 Nobel Prize in the area of Medicine/Physiology. In his Nobel Award accepting speech, Dr. Banting said “insulin is not a cure for diabetes, it is a treatment”. Interestingly, more than 90 years later, insulin still remains as a major treatment modality for diabetes. While the beneficial role of insulin in diabetes is well-recognized, enhanced level of insulin-mediated signaling could have deleterious consequences. A case in point is the harmful effect of insulin in cancer growth. Cellular function of insulin provides a clue for its harmful effect in cancer, where it is present at a higher level and highly active in mediating its function 1,2 . How does insulin function? Insulin allows most cells to absorb glucose from circulating blood and thereby it permits utilization of glucose for producing energy 3 . Physiological level of insulin is critical for maintaining adequate, not very high or very low levels of blood sugar. Insulin level rises on demand when blood sugar level is increased, following consumption of a meal. The signal of high glucose in the blood stream initiates insulin secretion from the pancreatic β cells, where it is synthesized and remains stored. By interacting with transmembrane insulin receptor (IR) proteins, insulin alters the permeability of cell membrane to glucose and promotes glucose adsorption. Insulin receptor is encoded by a single gene from which two isoforms of insulin receptor, IR-A and IR-B are generated via —————— *Corresponding author E-mail: rayb@missouri.edu Tel: 01-573-882-4461; Fax: 01-573-884-5414 Abbreviations: AMPK, cyclic AMP-dependent kinase; eIF4EBP1, eIF4E-binding protein 1; GLUT4, glucose transporter 4; IGF, insulin-like growth factor; IGF-BP, IGF-binding protein; IGF-R, insulin-like growth factor receptor; IR, insulin receptor; IRS-1, insulin receptor substrate-1; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PDK1, 3-phosphoinositide dependent protein kinase-1; PI3K, phosphoinositydyl 3-OH kinase; PIP3, phosphatidylinositol (3, 4, 5)-trisphosphate; Rheb, Ras homologue enriched in brain; S6K, ribosomal S6 kinase; TSC, tuberous sclerosis complex.