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The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling
Author(s) -
Scherbakov Alexander M.,
Sorokin Danila V.,
Tatarskiy Victor V.,
Prokhorov Nikolay S.,
Semina Svetlana E.,
Berstein Lev M.,
Krasil'nikov Mikhail A.
Publication year - 2016
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.1481
Subject(s) - metformin , ampk , estrogen receptor , cyclin d1 , pi3k/akt/mtor pathway , biguanide , tamoxifen , cancer research , protein kinase b , signal transduction , cancer cell , endocrinology , medicine , protein kinase a , breast cancer , chemistry , pharmacology , biology , cancer , kinase , microbiology and biotechnology , cell cycle , diabetes mellitus
Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti‐tumor drug for several types of cancer, including breast cancer. Anti‐tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate‐activated protein kinase (AMPK)—intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non‐sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin‐resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER‐positive MCF‐7 breast cancer cells and metformin‐resistant MCF‐7 subline (MCF‐7/M) developed due to long‐term metformin treatment. The transcriptional activity of NF‐κB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IκBα, (phospho)mTOR, cyclin D1, (phospho)Akt and ERα) and immunohistochemical analysis (E‐cadherin). We have found that: 1) metformin treatment of MCF‐7 cells is accompanied with the stimulation of AMPK and inhibition of growth‐related proteins including IκBα, NF‐κB, cyclin D1 and ERα; 2) long‐term metformin treatment lead to the appearance and progression of cross‐resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross‐resistance to metformin and tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the constitutive activation of Akt/Snail1/E‐cadherin signaling that opens new perspectives to overcome the metformin/tamoxifen resistance of breast cancer. © 2016 IUBMB Life, 68(4):281–292, 2016