Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2015 Mar 3;17(1):32. doi: 10.1186/s13058-015-0540-0

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

© Dowling et al.; licensee BioMed Central. 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

PMC Copyright notice

Proposed mechanism of action of metformin. (A) The potential mechanism(s) of antitumor action of metformin involves both direct (insulin-independent) and indirect (insulin-dependent) actions of the drug. The direct, insulin-independent effects of metformin involve activation of AMP-activated protein kinase (AMPK) in cancer cells via phosphorylation on Thr172 by liver kinase B1 (LKB1) and a subsequent reduction in mammalian target of rapamycin (mTOR) signaling, protein synthesis and cell proliferation. AMPK-independent actions of metformin may also contribute to its anticancer effects. The indirect, insulin-dependent effects are associated with reductions in circulating insulin levels mediated by inhibition of hepatic gluconeogenesis. The resulting decrease in insulin leads to reduced insulin receptor (IR)-mediated cancer cell signaling. (B) The results of the present study indicate that insulin-dependent effects of metformin are important in the clinical setting. Decreases in circulating insulin levels in metformin-treated patients, coupled with reductions in Akt (S473) and extracellular signal-regulated kinase 1/2 (ERK1/2; T202/Y204) phosphorylation in breast cancer cells, suggest reduced IR activation followed by decreases in phosphatidylinositol 3-kinase (PI3K) and Ras-mitogen-activated protein kinase (MAPK) signaling, cell proliferation and survival. MEK1/2, Mitogen-activated protein kinase kinase 1/2; mTORC1, Mammalian target of rapamycin complex 1; OCT1, Organic cation transporter 1.