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Insulin-like Growth Factor Receptor (insulin-like + growth_factor_receptor)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin-like growth factor receptor inhibition

INTERNATIONAL JOURNAL OF CANCER, Issue 11 2006
Ana S. Guerreiro
Abstract The potential of the novel insulin-like growth factor receptor (IGF-IR) inhibitor NVP-AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP-AEW541 with IC50 values ranging from 0.15 to 5 ,M. Experiments using an IGF-IR neutralizing antibody confirmed that the IGF-IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF-IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP-AEW541, while coexpression of the IGF-IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP-AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF-IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP-AEW541. IGF-I-stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP-AEW541, or by a combination of an inhibitor of phosphoinositide 3-kinase and rapamycin. In addition to its antiproliferative effects, NVP-AEW541 sensitized neuroblastoma cells to cisplatin-induced apoptosis. Together, our data demonstrate that NVP-AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation. © 2006 Wiley-Liss, Inc. [source]

Grb10 adapter protein as regulator of insulin-like growth factor receptor signaling

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2003
Andrea Morrione
Grb10 is a member of a superfamily of adapter proteins that includes Grb10, 7, 14, and a protein of Caenorhabditis elegans called Mig10. Grb10 proteins are binding partners for several trans-membrane tyrosine-kinase receptors, including the insulin-like growth factor receptor (IGF-IR) and the insulin receptor (IR). Many recent reports have suggested a very important role of Grb10 in regulating IGF-IR signaling. In this review, we will focus on the role of Grb10 in IGF-I-induced mitogenesis and we will discuss the recent findings that show the involvement of Grb10 in the regulation of ligand-induced ubiquitination, internalization, and stability of the IGF-IR. J. Cell. Physiol. 197: 307,311, 2003© 2003 Wiley-Liss, Inc. [source]

SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway

ARTHRITIS & RHEUMATISM, Issue 5 2010
Viktoria Gagarina
Objective The protein deacetylase SirT1 inhibits apoptosis in a variety of cell systems by distinct mechanisms, yet its role in chondrocyte death has not been explored. We undertook the present study to assess the role of SirT1 in the survival of osteoarthritic (OA) chondrocytes in humans. Methods SirT1, protein tyrosine phosphatase 1B (PTP1B), and PTP1B mutant expression plasmids as well as SirT1 small interfering RNA (siRNA) and PTP1B siRNA were transfected into primary human chondrocytes. Levels of apoptosis were determined using flow cytometry, and activation of components of the insulin-like growth factor receptor (IGFR)/Akt pathway was assessed using immunoblotting. OA and normal knee cartilage samples were subjected to immunohistochemical analysis. Results Expression of SirT1 in chondrocytes led to increased chondrocyte survival in either the presence or the absence of tumor necrosis factor ,/actinomycin D, while a reduction of SirT1 by siRNA led to increased chondrocyte apoptosis. Expression of SirT1 in chondrocytes led to activation of IGFR and the downstream kinases phosphatidylinositol 3-kinase, phosphoinosite-dependent protein kinase 1, mTOR, and Akt, which in turn phosphorylated MDM2, inhibited p53, and blocked apoptosis. Activation of IGFR occurs at least in part via SirT1-mediated repression of PTP1B. Expression of PTP1B in chondrocytes increased apoptosis and reduced IGFR phosphorylation, while down-regulation of PTP1B by siRNA significantly decreased apoptosis. Examination of cartilage from normal donors and OA patients revealed that PTP1B levels are elevated in OA cartilage in which SirT1 levels are decreased. Conclusion For the first time, it has been demonstrated that SirT1 is a mediator of human chondrocyte survival via down-regulation of PTP1B, a potent proapoptotic protein that is elevated in OA cartilage. [source]

Crystallization and preliminary X-ray analysis of the complexes between a Fab and two forms of human insulin-like growth factor II

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 9 2009
Janet Newman
Elevated expression of insulin-like growth factor II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon and liver cancer. As IGF-II can deliver a mitogenic signal through both the type 1 insulin-like growth factor receptor (IGF-IR) and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is an attractive therapeutic option. One method of doing this would be to find antibodies that bind tightly and specifically to the peptide, which could be used as protein therapeutics to lower the peptide levels in vivo and/or to block the peptide from binding to the IGF-IR or IR-A. To address this, Fabs were selected from a phage-display library using a biotinylated precursor form of the growth factor known as IGF-IIE as a target. Fabs were isolated that were specific for the E-domain C-terminal extension and for mature IGF-II. Four Fabs selected from the library were produced, complexed with IGF-II and set up in crystallization trials. One of the Fab,IGF-II complexes (M64-F02,IGF-II) crystallized readily, yielding crystals that diffracted to 2.2,Å resolution and belonged to space group P212121, with unit-cell parameters a = 50.7, b = 106.9, c = 110.7,Å. There was one molecule of the complete complex in the asymmetric unit. The same Fab was also crystallized with a longer form of the growth factor, IGF-IIE. This complex crystallized in space group P212121, with unit-cell parameters a = 50.7, b = 107, c = 111.5,Å, and also diffracted X-rays to 2.2,Å resolution. [source]

Chemosensitization of human prostate cancer using antisense agents targeting the type 1 insulin-like growth factor receptor

BJU INTERNATIONAL, Issue 3 2003
G.O. Hellawell
OBJECTIVE To assess the effect of the downregulation of type 1 insulin-like growth factor receptor (IGF1R) on the chemosensitivity of prostate cancer cells. IGF1R is overexpressed by prostate cancer compared with benign prostatic epithelium and IGF1R expression commonly persists in androgen-independent metastatic disease at levels comparable to those in the primary. MATERIALS AND METHODS Human androgen-independent DU145 prostate cancer cells were transfected with IGF1R antisense oligonucleotides or antisense RNA. Transfected cultures were treated with cisplatin, mitoxantrone, paclitaxel or vehicle control, and survival measured using a clonogenic assay. RESULTS Both antisense strategies suppressed IGF1R protein levels to 30,50% of those in control cultures. This was associated with 1.5,2-fold enhancement of sensitivity to cisplatin, mitoxantrone and paclitaxel, and an increase in cisplatin-induced apoptosis. CONCLUSION This approach has potential for development as a clinical treatment for advanced prostate cancer and other chemoresistant tumours. [source]

Various components of the insulin-like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patients

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2008
Judith M. de Bont
Abstract The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas. © 2008 Wiley-Liss, Inc. [source]

Growth factors and proliferation of cultured rat gingival cells in response to cyclosporin A

JOURNAL OF PERIODONTAL RESEARCH, Issue 1 2005
Takumasa Yoshida
Objective:, The prominent side-effect of cyclosporin A, an immunosuppressive drug, in oral tissues is gingival outgrowth, although the exact mechanism underlying this side-effect is unclear. The main purposes of the present study were to determine whether cyclosporin A induced the gingival outgrowth by promoting proliferation of gingival cells and whether growth factors such as transforming growth factor-,s (TGF-,s), fibroblast growth factor-2 (FGF-2), platelet-derived growth factors (PDGFs), and insulin-like growth factors (IGFs) are involved in the possible changes in the proliferation of gingival cells induced by cyclosporin A. Methods:, Cells isolated from rat gingival tissues were cultured with cyclosporin A or IGF-I for 3 days. The effects of cyclosporin A or IGF-I on the proliferation of cultured rat gingival cells were analyzed with a CellTiter 96 proliferation assay kit. The mRNA expression levels for TGF-,s, FGF-2, PDGFs, IGFs, insulin-like growth factor receptors (IGFRs), and insulin-like growth factor binding proteins (IGFBPs) in the rat gingival cells treated with cyclosporin A were measured using competitive reverse transcription,polymerase chain reaction (RT,PCR). Results:, Cyclosporin A induced 23,25% (p < 0.001) increases in the proliferation of rat gingival cells and approximately 130% (p < 0.05) and 60% (p < 0.05) elevations in the mRNA expression levels for TGF-,1 and FGF-2, respectively. On the other hand, exogenous IGF-I induced 8,11% (p < 0.05) increases in the proliferation, but cyclosporin A induced 30,80% (p < 0.05,0.01) reductions in the mRNA expression levels for endogenous IGF-I, IGFR1, IGFBP2, IGFBP3, IGFBP5, and IGFBP6. Conclusions:, Cyclosporin A stimulates the proliferation of rat gingival cells. TGF-,1 and FGF-2 could be involved, but IGFs, IGFRs and IGFBPs could not be directly involved in this cyclosporin A induced-stimulation of the gingival cell proliferation. [source]