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    Metformin Inhibits Androgen-Induced IGF-IR Up-Regulation in Prostate Cancer Cells by Disrupting Membrane-Initiated Androgen Signaling

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    Genre
    Journal article
    Date
    2014-04-01
    Author
    Malaguarnera, Roberta
    Sacco, Antonella
    Morcavallo, Alaide
    Squatrito, Sebastiano
    Migliaccio, Antimo
    Morrione, Andrea cc
    Maggiolini, Marcello
    Belfiore, Antonino
    Department
    Biology
    Subject
    Cancer
    Oncogenes
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/7091
    
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    DOI
    https://doi.org/10.1210/en.2013-1925
    Abstract
    We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR+ LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy.
    Citation
    Roberta Malaguarnera, Antonella Sacco, Alaide Morcavallo, Sebastiano Squatrito, Antimo Migliaccio, Andrea Morrione, Marcello Maggiolini, Antonino Belfiore, Metformin Inhibits Androgen-Induced IGF-IR Up-Regulation in Prostate Cancer Cells by Disrupting Membrane-Initiated Androgen Signaling, Endocrinology, Volume 155, Issue 4, 1 April 2014, Pages 1207–1221, https://doi.org/10.1210/en.2013-1925
    Citation to related work
    Oxford University Press
    Has part
    Endocrinology, Vol. 155, No. 4
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/7071
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