The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy

Vigneri, Paolo; Tirrò, Elena; Pennisi, Maria Stella; Massimino, Michele; Stella, Stefania; Romano, Chiara; Manzella, Livia

doi:10.3389/fonc.2015.00230

Cited by 150 publications

(136 citation statements)

References 62 publications

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“…This is important to recognize because hybrid receptors form as a result of heterodimerization (IGF and INSR) and homodimerization (INSRA and INSRB) resulting in six different receptor subtypes that insulin might interact with (Singh, Ale, & Bast, ). Normal and immortalized cell lines have been shown to express hybrid receptors that are frequently the predominant receptor present (Belfiore et al, ; Frasca, Pandini, Vigneri, & Goldfine, ; Pandini et al, ; Vigneri et al, ). Moreover, hybrid receptor signaling may occur through non‐kinase pathways, being different from IGF1 and/or insulin receptor signaling (Belfiore et al, ; Crudden, Girnita, & Girnita, ).…”

Section: Discussionmentioning

confidence: 99%

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Dean

Rose

2018

Molecular Reproduction Devel

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Glycogen synthesis by mink uterine epithelial cells is stimulated by estradiol (E ) during estrus, although the mechanism/s through which the steroid promotes glycogen accumulation are unknown. Our aim was to determine if insulin is required for E induced glycogen synthesis by an immortalized mink uterine epithelial cell line (GMMe). We show that the cells expressed the genes for glycogen metabolizing enzymes (hexokinase 1, glucose-6-phosphatase 3, glycogen synthase 1, and glycogen phosphorylase-muscle), receptors for insulin, insulin-like growth factor 1 and E (Esr1). Interestingly, treatment of cells with E alone failed to stimulate glycogen production, whereas supraphysiological concentrations of insulin (50 μg/ml) only, significantly increased glycogen content. Moreover, insulin + E increased glycogen content when compared to insulin alone (p < 0.05), an affect that was blocked when cells were treated with the pure E receptor antagonist ICI 182,780. Glycogen synthesis in response to insulin was significantly inhibited when cells were pre-treated with picropodophyllotoxin, an IGF1R antagonist. Treatment of cells with LY294002, a phosphatidylinositol 3-kinase (PI3K) antagonist, blocked insulin's effects on glycogen production whereas treatment with U0126, an inhibitor of mitogen activated kinase-kinase (MEK1/2) was without effect. These findings suggest to us that the affects of E on glycogen synthesis by GMMe cells is mediated through Esr1 and increased responsiveness of the cells to insulin. Because picropodophylotoxin blocked the effects of insulin on glycogen production, and both insulin and IGF1 act through PI3K, it is possible that IGF1 plays a role in glycogen production by these cells.

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Section: Discussionmentioning

confidence: 99%

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Dean

Rose

2018

Molecular Reproduction Devel

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“…IGF1R over expression is associated with an increased risk of recurrence of non-small cell lung cancer (NSCLC) (8). Additionally, high levels of circulating IGF1 is linked to an increased risk of development of breast, prostate, and colorectal cancers (5,9). However, several pharmacological agents, monoclonal antibodies and small molecule inhibitors targeting this axis have failed to show significant benefit on overall survival (10).…”

Section: Introductionmentioning

confidence: 99%

Regulation of insulin-like growth factor receptors by Ubiquilin1

Kurlawala

Dunaway

Shah

et al. 2017

Biochemical Journal

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Insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase that mediates growth, proliferation and survival. Dysregulation of IGF pathway contributes to initiation, progression and metastasis of cancer and is also involved in diseases of glucose metabolism, such as Diabetes. We have identified Ubiquilin1 (UBQLN1) as a novel interaction partner of IGF1R, IGF2R and Insulin Receptor. UBQLN family of proteins have been studied primarily in the context of protein quality control and in the field of neurodegenerative disorders. Our laboratory discovered a link between UBQLN1 function and tumorigenesis, such that UBQLN1 is lost and under-expressed in 50% of human lung adenocarcinoma cases. We demonstrate here that UBQLN1 regulates expression and activity of IGF1R. Following loss of UBQLN1 in lung adenocarcinoma cells, there is accelerated loss of IGF1R. Despite decreased levels of total receptors, the ratio of active:total receptors is higher in cells that lack UBQLN1. UBQLN1 also regulates Insulin Receptor (INSR) and IGF2R post-stimulation with ligand. We conclude that UBQLN1 is essential for normal regulation of IGF receptors. UBQLN1 deficient cells demonstrate increased cell viability compared to control when serum starved and stimulation of IGF pathway in these cells increased their migratory potential by 3-fold. As the IGF pathway is involved in processes of normal growth, development, metabolism and cancer progression, understanding its regulation by Ubiquilin1 can be of tremendous value to many disciplines.

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“…exhibited toxicity at higher concentrations due to drug interactions with healthy, EGFR-expressing cells. By adding a specificity for a co-expressing TAA, such as IGFR, 61 and carefully calibrating the affinities of the anti-TAA paratopes to maximize tumor-cell selectivity, one could reduce such adverse effects. With a fourth paratope, such a molecule could also target a preservative protein, such as human serum albumin (HSA), to lengthen serum half-life and reduce the frequency of drug administration.…”

Section: Discussionmentioning

confidence: 99%

Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments

Egan

Diem²,

Weldon³

et al. 2016

mAbs

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Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the instability of the antibody fragments of which they consist, 2) undesired inter-subunit associations, and 3) the need to include recombinant heterodimerization domains that confer distribution-impairing bulk or enhance immunogenicity. In this paper, we describe a broadly-applicable method for the stabilization of human or humanized antibody Fv fragments that entails replacing framework region IV of a Vκ1/VH3-consensus Fv framework with the corresponding germ-line sequence of a λ-type VL chain. We then used this stable Fv framework to generate a novel heterodimeric multispecific antibody format that assembles by cognate VL/VH associations between 2 split variable domains in the core of the complex. This format, termed multispecific antibody-based therapeutics by cognate heterodimerization (MATCH), can be applied to produce homogeneous and highly stable antibody-derived molecules that simultaneously bind 4 distinct antigens. The heterodimeric design of the MATCH format allows efficient in-format screening of binding domain combinations that result in maximal cooperative activity.

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The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy

Cited by 150 publications

References 62 publications

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Activation of the IGF1 receptor stimulates glycogen synthesis by mink uterine epithelial cells

Regulation of insulin-like growth factor receptors by Ubiquilin1

Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments

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