Insulin, insulin receptors, and cancer

  title={Insulin, insulin receptors, and cancer},
  author={Riccardo Vigneri and Ira D. Goldfine and Lucia Frittitta},
  journal={Journal of Endocrinological Investigation},
Insulin is a major regulator of cell metabolism but, in addition, is also a growth factor. Insulin effects in target cells are mediated by the insulin receptor (IR), a transmembrane protein with enzymatic (tyrosine kinase) activity. The insulin receptor, however, is represented by a heterogeneous family of proteins, including two different IR isoforms and also hybrid receptors resulting from the IR hemireceptor combination with a hemireceptor of the cognate IGF-1 receptor. These different… 
Insulin Receptor Isoforms in Cancer
The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway
Targeting Insulin Receptor in Breast Cancer Using Small Engineered Protein Scaffolds
Three Gp2 variants with low nanomolar affinity and specific binding to cell surface InsR are identified, which are the first nonimmunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling.
The Roles of the IGF Axis in the Regulation of the Metabolism: Interaction and Difference between Insulin Receptor Signaling and IGF-I Receptor Signaling
This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906.
Structural Perspectives of Insulin Receptor Isoform-Selective Insulin Analogs
Structural perspectives for the design of specific insulin analogs with a preferential binding to IR-B are offered, which have the potential to restore more natural metabolic homeostasis in diabetes.
Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities.
An insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the "metabolic" IR-B isoform is discovered.
Galanin enhanced insulin-mediated intracellular signaling by regulating the stability of membrane-localized insulin/IR.
The cell characteristics and signaling profiles of insulin in the intestinal cell model are studied, and it is found that insulin can be internalized into the cytoplasm in a time-dependent manner and galanin could increase the time of insulin acting on the cell membrane.
Development of a novel insulin receptor (IR) antagonist that exhibits anti-breast tumor activity
A new method to develop the insulin receptor (IR) antagonist (AK98) was proposed, and a series of experiments showed that the anti-idiotypic antibody (AK 98) exhibited good antagonistic activity against IR.
The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides
This review is expected to provide useful information for a better understanding of human IR-related diseases, as well as to facilitate the development of novel small-molecule activators and inhibitors of the IR for use as medicines or pesticides.
Insulin-like Growth Factor 2 mRNA-Binding Protein 2—a Potential Link Between Type 2 Diabetes Mellitus and Cancer
Accumulating evidence revealed that IGF2BP2 mediates the pathogenesis of T2DM and cancer by regulating glucose metabolism, insulin sensitivity, and tumorigenesis.


The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer.
  • A. Belfiore
  • Biology, Medicine
    Current pharmaceutical design
  • 2007
The concept that hyperinsulinemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmachological approaches to avoid an increased risk for cancer is underline.
Insulin Receptor Isoform A, a Newly Recognized, High-Affinity Insulin-Like Growth Factor II Receptor in Fetal and Cancer Cells
The present study found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin, indicating that there are two receptors for IGF- II, both IGF-I-R and IR- a, and suggests that interaction of IGF-ii withIR-A may play a role both in fetal growth and cancer biology.
Insulin/Insulin-like Growth Factor I Hybrid Receptors Have Different Biological Characteristics Depending on the Insulin Receptor Isoform Involved*
It was found that Hybrid-Rs containing IR-A (Hybrid-RsA) bound to and were activated by IGF-I, IGF-II, and insulin, and cell proliferation and migration in response to both insulin and IGFs were more effectively stimulated in Hybrid-RA-containing cells than in hybrid-RB- containing cells.
Biological Effects of Insulin and Its Analogs on Cancer Cells With Different Insulin Family Receptor Expression
In vitro insulin is an effective growth factor for all cancer cells but the biological response to insulin cannot be predicted on the basis of receptor expression levels, and these observations should be taken in account when deciding treatment for diabetic patients who are at risk of undiscovered cancer or survivors of oncological diseases.
Insulin and hybrid insulin/IGF receptors are major regulators of breast cancer cells.
This chapter will review the latest developments in the understanding of the IR in breast cancer as insulin signals breast cancer cells via its own receptor, and new data indicate that the fetal form of theIR (IR-A) is expressed in breast cancers.
Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.
Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients.
Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells.
The formation of hybrid insulin/insulin-like growth factor-I(IGF-I) receptors in transfected rodent fibroblasts is demonstrated by examining reactivity with species- and receptor-specific monoclonal antibodies, and responses to these ligands were asymmetrical.
Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling.
The insulin receptor may play a role in the regulation of ovarian cancer cell growth and real-time PCR analyses confirm that insulin receptor isoform A expression predominates over isoform B expression in the ovarian carcinoma cell lines.
Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway.
Proinsulin is a selective IR-A ligand and may induce biological effects through this IR isoform through which it binds to and activates the two insulin receptor (IR) isoforms.
Insulin Analogs and Cancer
Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to receptors for insulin but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin.