PMID- 26892736 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20211203 IS - 1521-6551 (Electronic) IS - 1521-6543 (Linking) VI - 68 IP - 4 DP - 2016 Apr TI - The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling. PG - 281-92 LID - 10.1002/iub.1481 [doi] AB - 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-kappaB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IkappaBalpha, (phospho)mTOR, cyclin D1, (phospho)Akt and ERalpha) 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 IkappaBalpha, NF-kappaB, cyclin D1 and ERalpha; 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. CI - (c) 2016 International Union of Biochemistry and Molecular Biology. FAU - Scherbakov, Alexander M AU - Scherbakov AM AD - Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, N.N. Blokhin Cancer Research Centre, Moscow, Russia. FAU - Sorokin, Danila V AU - Sorokin DV AD - Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Moscow, Russia. FAU - Tatarskiy, Victor V Jr AU - Tatarskiy VV Jr AD - Laboratory of Cell Death Mechanisms, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Moscow, Russia. FAU - Prokhorov, Nikolay S AU - Prokhorov NS AD - Laboratory of Microbial Viruses, S.N. Winogradsky Institute of Microbiology, Russian Academy of Sciences, Moscow, Russia. FAU - Semina, Svetlana E AU - Semina SE AD - Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Moscow, Russia. FAU - Berstein, Lev M AU - Berstein LM AD - Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St, Petersburg, Russia. FAU - Krasil'nikov, Mikhail A AU - Krasil'nikov MA AD - Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Moscow, Russia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160219 PL - England TA - IUBMB Life JT - IUBMB life JID - 100888706 RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (CCND1 protein, human) RN - 0 (Cadherins) RN - 0 (Estrogen Receptor alpha) RN - 0 (Hypoglycemic Agents) RN - 0 (NF-kappa B) RN - 0 (SNAI1 protein, human) RN - 0 (Snail Family Transcription Factors) RN - 094ZI81Y45 (Tamoxifen) RN - 136601-57-5 (Cyclin D1) RN - 9100L32L2N (Metformin) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/genetics/metabolism MH - Antineoplastic Agents, Hormonal/*pharmacology MH - Cadherins/genetics/metabolism MH - Cell Proliferation/drug effects MH - Cyclin D1/genetics/metabolism MH - Drug Resistance, Neoplasm/*drug effects/genetics MH - Estrogen Receptor alpha/genetics/metabolism MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - MCF-7 Cells MH - Metformin/*pharmacology MH - NF-kappa B/genetics/metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Signal Transduction MH - Snail Family Transcription Factors/genetics/metabolism MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Tamoxifen/*pharmacology OTO - NOTNLM OT - breast cancer OT - cell signaling OT - epithelial-mesenchymal transition OT - metformin OT - signal transduction OT - signal transduction pathways EDAT- 2016/02/20 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/02/20 06:00 PHST- 2015/11/14 00:00 [received] PHST- 2016/01/10 00:00 [accepted] PHST- 2016/02/20 06:00 [entrez] PHST- 2016/02/20 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - 10.1002/iub.1481 [doi] PST - ppublish SO - IUBMB Life. 2016 Apr;68(4):281-92. doi: 10.1002/iub.1481. Epub 2016 Feb 19.