Combined treatment of MCF-7 cells with AICAR and methotrexate, arrests cell cycle and reverses warburg metabolism through AMP-activated protein kinase (AMPK) and FOXO1

Tamás Fodor, Magdolna Szántó, Omar Abdul-Rahman, Lilla Nagy, Ádám Dér, Borbála Kiss, P. Bai

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMPactivated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

Original languageEnglish
Article numbere0150232
JournalPLoS One
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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methotrexate
AMP-activated protein kinase
AMP-Activated Protein Kinases
MCF-7 Cells
Cell Cycle Checkpoints
Metabolism
Methotrexate
breast neoplasms
Cells
Breast Neoplasms
metabolism
Cell proliferation
glycolysis
Glycolysis
cells
cell proliferation
Cell Proliferation
oxidation
Pentoses
Antimetabolites

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Combined treatment of MCF-7 cells with AICAR and methotrexate, arrests cell cycle and reverses warburg metabolism through AMP-activated protein kinase (AMPK) and FOXO1. / Fodor, Tamás; Szántó, Magdolna; Abdul-Rahman, Omar; Nagy, Lilla; Dér, Ádám; Kiss, Borbála; Bai, P.

In: PLoS One, Vol. 11, No. 2, e0150232, 01.02.2016.

Research output: Contribution to journalArticle

Fodor, Tamás ; Szántó, Magdolna ; Abdul-Rahman, Omar ; Nagy, Lilla ; Dér, Ádám ; Kiss, Borbála ; Bai, P. / Combined treatment of MCF-7 cells with AICAR and methotrexate, arrests cell cycle and reverses warburg metabolism through AMP-activated protein kinase (AMPK) and FOXO1. In: PLoS One. 2016 ; Vol. 11, No. 2.
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