Research Papers:

Metformin-induced metabolic reprogramming of chemoresistant ALDHbright breast cancer cells

Mario Cioce, MariaCristina Valerio, Luca Casadei, Claudio Pulito, Andrea Sacconi, Federica Mori, Francesca Biagioni, Cesare Manetti, Paola Muti, Sabrina Strano and Giovanni Blandino _

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Oncotarget. 2014; 5:4129-4143. https://doi.org/10.18632/oncotarget.1864

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Mario Cioce1*, MariaCristina Valerio2*, Luca Casadei2, Claudio Pulito3, Andrea Sacconi4, Federica Mori 3, Francesca Biagioni4, Cesare Manetti2 , Paola Muti5, Sabrina Strano3, and Giovanni Blandino4.

1 Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY USA

2 Department of Chemistry, University of Rome ‘La Sapienza’, 00185 Rome, Italy

3 Molecular Chemoprevention Group, Italian National Cancer Institute “Regina Elena”, Rome, Italy

4 Translational Oncogenomic Unit, Italian National Cancer Institute “Regina Elena”, Rome, Italy

5 Department of Oncology, McMaster University, Hamilton, Ontario, L8V 5C2, Canada

* These two authors contributed equally


Giovanni Blandino , email:

Keywords: Metformin, metabolism, chemoresistance, ALDH, metabolic reprogramming, cancer

Received: January 22, 2014 Accepted: March 24, 2014 Published: March 26, 2014


Metabolic remodeling is a hallmark of cancer progression and may affect tumor chemoresistance. Here we investigated by 1H-NMR/PCA analysis the metabolic profile of chemoresistant breast cancer cell subpopulations (ALDHbright cells) and their response to metformin, a promising anticancer metabolic modulator. The purified ALDHbright cells exhibited a different metabolic profile as compared to their chemosensitive ALDHlow counterparts. Metformin treatment strongly affected the metabolism of the ALDHbright cells thereby affecting, among the others, the glutathione metabolism, whose upregulation is a feature of progenitor-like, chemoresistant cell subpopulations. Globally, metformin treatment reduced the differences between ALDHbright and ALDHlow cells, making the former more similar to the latter. Metformin broadly modulated microRNAs in the ALDHbright cells, with a large fraction of them predicted to target the same metabolic pathways experimentally identified by 1H-NMR. Additionally, metformin modulated the levels of c-MYC and IRS-2, and this correlated with changes of the microRNA-33a levels. In summary, we observed, both by 1H-NMR and microRNA expression studies, that metformin treatment reduced the differences between the chemoresistant ALDHbright cells and the chemosensitive ALDHlow cells. This works adds on the potential therapeutic relevance of metformin and shows the potential for metabolic reprogramming to modulate cancer chemoresistance.

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