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R1507, an anti-insulin-like growth factor-1 receptor (IGF-1R) antibody, and EWS/FLI-1 siRNA in Ewing's sarcoma: convergence at the IGF/IGFR/Akt axis.

Abstract

A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt.

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  • Authors

    Huang HJ, Angelo LS, Rodon J, Sun M, Kuenkele KP, Parsons HA, Trent JC, Kurzrock R

    Source

    PloS one 6:10 2011 pg e26060

    MeSH

    Antibodies, Monoclonal
    Apoptosis
    Cell Line, Tumor
    Cell Proliferation
    Colony-Forming Units Assay
    Down-Regulation
    HEK293 Cells
    Humans
    Insulin Receptor Substrate Proteins
    Insulin-Like Growth Factor Binding Protein 3
    Insulin-Like Growth Factor II
    Oncogene Proteins, Fusion
    Phosphorylation
    Polymorphism, Genetic
    Protein Structure, Tertiary
    Proto-Oncogene Protein c-fli-1
    Proto-Oncogene Proteins c-akt
    RNA, Small Interfering
    RNA-Binding Protein EWS
    Receptor, IGF Type 1
    Receptor, IGF Type 2
    Reproducibility of Results
    Sarcoma, Ewing
    Signal Transduction
    Somatomedins
    Transfection

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22022506