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dc.creatorMalaguarnera, Roberta
dc.creatorSacco, Antonella
dc.creatorMorcavallo, Alaide
dc.creatorSquatrito, Sebastiano
dc.creatorMigliaccio, Antimo
dc.creatorMorrione, Andrea
dc.creatorMaggiolini, Marcello
dc.creatorBelfiore, Antonino
dc.date.accessioned2021-11-09T15:40:34Z
dc.date.available2021-11-09T15:40:34Z
dc.date.issued2014-04-01
dc.identifier.citationRoberta 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
dc.identifier.issn1945-7170
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/7071
dc.identifier.urihttp://hdl.handle.net/20.500.12613/7091
dc.description.abstractWe 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.
dc.format.extent15 pages
dc.languageEnglish
dc.language.isoeng
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartEndocrinology, Vol. 155, No. 4
dc.relation.isreferencedbyOxford University Press
dc.rightsAll Rights Reserved
dc.subjectCancer
dc.subjectOncogenes
dc.titleMetformin Inhibits Androgen-Induced IGF-IR Up-Regulation in Prostate Cancer Cells by Disrupting Membrane-Initiated Androgen Signaling
dc.typeText
dc.type.genreJournal article
dc.description.departmentBiology
dc.relation.doihttps://doi.org/10.1210/en.2013-1925
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.schoolcollegeTemple University. College of Science and Technology
dc.creator.orcidMorrione|0000-0002-2319-7884
dc.temple.creatorMorrione, Andrea
refterms.dateFOA2021-11-09T15:40:34Z


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