Journal Article

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

Pollak, Michael N, Zakikhani, Mahvash, Piura, Esther, Blouin, Marie-José

2010

Overview

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.

• Publisher: Boston : Springer US,Springer US,Springer,Springer Nature B.V
• Subject: AMPK / Antineoplastic Agents / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Biological and medical sciences / Blotting, Western / Breast cancer / Breast Neoplasms / Breast Neoplasms - metabolism / Brief Report / Cancer research / Cancer therapies / Cell growth / Cell Line, Tumor / Cell Proliferation / Cell Proliferation - drug effects / Cell Separation / drug effects / Drugs / Enzyme Activation / Enzyme Activation - drug effects / Female / Flow Cytometry / Gynecology. Andrology. Obstetrics / Humans / Intracellular Signaling Peptides and Proteins / Intracellular Signaling Peptides and Proteins - drug effects / Intracellular Signaling Peptides and Proteins - metabolism / IRS-1 / Mammary gland diseases / Medical sciences / Medicine / Medicine & Public Health / metabolism / Metformin / Metformin - pharmacology / Oncology / pharmacology / Phosphorylation / Phosphorylation - drug effects / Proliferation / Protein biosynthesis / Protein Serine-Threonine Kinases / Protein-Serine-Threonine Kinases - drug effects / Protein-Serine-Threonine Kinases - metabolism / Proto-Oncogene Proteins c-akt / Proto-Oncogene Proteins c-akt - drug effects / Proto-Oncogene Proteins c-akt - metabolism / Rapamycin / Signal Transduction / Signal Transduction - drug effects / Sirolimus / Sirolimus - pharmacology / TOR Serine-Threonine Kinases / Transfection / Tumors