Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.

Authors

Roberta Malaguarnera, Department of Health Sciences, University of Catanzaro, Campus Universitario, Viale Europa, Località Germaneto, 88100 Catanzaro, ItalyFollow
Antonella Sacco, Department of Health Sciences, University of Catanzaro, Campus Universitario, Viale Europa, Località Germaneto, 88100 Catanzaro, Italy
Alaide Morcavallo, Department of Health Sciences, University of Catanzaro, Campus Universitario, Viale Europa, Località Germaneto, 88100 Catanzaro, ItalyFollow
Sebastiano Squatrito, Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi-Nesima Hospital, 95125 Catania, Italy
Antimo Migliaccio, Department of General Pathology, II University of Naples, Via L. De Crecchio, 7-80138 Naples, Italy
Andrea Morrione, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Marcello Maggiolini, Department of Pharmaco-Biology, University of Calabria, 87030 Rende, ItalyFollow
Antonino Belfiore, Department of Health Sciences, University of Catanzaro, Campus Universitario, Viale Europa, Località Germaneto, 88100 Catanzaro, ItalyFollow

Document Type

Article

Publication Date

4-1-2014

Comments

This article has been peer reviewed. It was published in: Endocrinology.

Volume 155, Issue 4, April 2014, Pages 1207-1221.

The published version is available at DOI: 10.1210/en.2013-1925

Copyright © 2014 by The Endocrine Society

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.

Recommended Citation

Malaguarnera, Roberta; Sacco, Antonella; Morcavallo, Alaide; Squatrito, Sebastiano; Migliaccio, Antimo; Morrione, Andrea; Maggiolini, Marcello; and Belfiore, Antonino, "Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling." (2014). Department of Urology Faculty Papers. Paper 26.
https://jdc.jefferson.edu/urologyfp/26

PubMed ID

24437490