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Erschienen in: Breast Cancer Research and Treatment 1/2010

01.08.2010 | Brief Report

Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells

verfasst von: Mahvash Zakikhani, Marie-José Blouin, Esther Piura, Michael N. Pollak

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2010

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Abstract

Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5′- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser789, a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser789 phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.
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Metadaten
Titel
Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells
verfasst von
Mahvash Zakikhani
Marie-José Blouin
Esther Piura
Michael N. Pollak
Publikationsdatum
01.08.2010
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 1/2010
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-010-0763-9

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