Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells

Giuseppe Pandini, Rossana Mineo, Francesco Frasca, Charles Roberts, Marco Marcelli, Riccardo Vigneri, Antonino Belfiore

    Research output: Contribution to journalArticle

    151 Citations (Scopus)

    Abstract

    In this study, we show that androgens up-regulate insulin-like growth factor-I receptor (IGF-IR) expression and sensitize prostate cancer cells to the biological effects of IGF-I. Both dihydrotestosterone and the synthetic androgen R1881 induced an ∼6-fold increase in IGF-IR expression in androgen receptor (AR)-positive prostate cancer cells LNCaP. In accordance with IGF-IR up-regulation, treatment with the nonmetabolizable androgen R1881 sensitized LNCaP cells to the mitogenic and motogenic effects of IGF-I, whereas an IGF-IR blocking antibody effectively inhibited these effects. By contrast, these androgens did not affect IGF-IR expression in AR-negative prostate cancer cells PC-3. Reintroduction of AR into PC-3 cells by stable transfection restored the androgen effect on IGF-IR up-regulation. R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide). Two other AR antagonists, cyproterone acetate and OH-flutamide, were much less effective. Androgen-induced IGF-IR up-regulation was not dependent on AR genomic activity, because two AR mutants, AR-C619Y and AR-C574R, devoid of DNA binding activity and transcriptional activity were still able to elicit IGF-IR up-regulation in HEK293 kidney cells in response to androgens. Moreover, androgen-induced IGF-IR up-regulation involves the activation of the Src-extracellular signal-regulated kinase pathway, because it was inhibited by both the Src inhibitor PP2 and the MEK-1 inhibitor PD98059. The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action. Anti-androgen therapy may be only partially effective, or almost ineffective, in blocking important biological effects of androgens, such as activation of the IGF system.

    Original languageEnglish (US)
    Pages (from-to)1849-1857
    Number of pages9
    JournalCancer Research
    Volume65
    Issue number5
    DOIs
    StatePublished - Mar 1 2005

    Fingerprint

    IGF Type 1 Receptor
    Androgens
    Prostatic Neoplasms
    Up-Regulation
    Androgen Receptors
    Metribolone
    Fibroblast Growth Factor 8
    Androgen Receptor Antagonists
    Insulin-Like Growth Factor I
    Testosterone Congeners
    Flutamide
    Cyproterone Acetate
    Blocking Antibodies
    Dihydrotestosterone
    HEK293 Cells
    Mitogen-Activated Protein Kinase Kinases
    Extracellular Signal-Regulated MAP Kinases
    Transfection

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Pandini, G., Mineo, R., Frasca, F., Roberts, C., Marcelli, M., Vigneri, R., & Belfiore, A. (2005). Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Research, 65(5), 1849-1857. https://doi.org/10.1158/0008-5472.CAN-04-1837

    Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. / Pandini, Giuseppe; Mineo, Rossana; Frasca, Francesco; Roberts, Charles; Marcelli, Marco; Vigneri, Riccardo; Belfiore, Antonino.

    In: Cancer Research, Vol. 65, No. 5, 01.03.2005, p. 1849-1857.

    Research output: Contribution to journalArticle

    Pandini, G, Mineo, R, Frasca, F, Roberts, C, Marcelli, M, Vigneri, R & Belfiore, A 2005, 'Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells', Cancer Research, vol. 65, no. 5, pp. 1849-1857. https://doi.org/10.1158/0008-5472.CAN-04-1837
    Pandini, Giuseppe ; Mineo, Rossana ; Frasca, Francesco ; Roberts, Charles ; Marcelli, Marco ; Vigneri, Riccardo ; Belfiore, Antonino. / Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. In: Cancer Research. 2005 ; Vol. 65, No. 5. pp. 1849-1857.
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