title: Metformin-induced metabolic reprogramming of chemoresistant ALDHbright breast cancer cells.
abstract: 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.
authors: Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY USA. These two authors contributed equally.
authors: Mario
authors: M
authors: Cioce
authors: Department of Chemistry, University of Rome 'La Sapienza', 00185 Rome, Italy. These two authors contributed equally.
authors: MariaCristina
authors: M
authors: Valerio
authors: Department of Chemistry, University of Rome 'La Sapienza', 00185 Rome, Italy.
authors: Luca
authors: L
authors: Casadei
authors: Molecular Chemoprevention Group, Italian National Cancer Institute "Regina Elena", Rome, Italy.
authors: Claudio
authors: C
authors: Pulito
authors: Translational Oncogenomic Unit, Italian National Cancer Institute "Regina Elena", Rome, Italy.
authors: Andrea
authors: A
authors: Sacconi
authors: Molecular Chemoprevention Group, Italian National Cancer Institute "Regina Elena", Rome, Italy.
authors: Federica
authors: F
authors: Mori
authors: Translational Oncogenomic Unit, Italian National Cancer Institute "Regina Elena", Rome, Italy.
authors: Francesca
authors: F
authors: Biagioni
authors: Department of Chemistry, University of Rome 'La Sapienza', 00185 Rome, Italy.
authors: Cesare
authors: C
authors: Manetti
authors: Department of Oncology, McMaster University, Hamilton, Ontario, L8V 5C2, Canada.
authors: Paola
authors: P
authors: Muti
authors: Translational Oncogenomic Unit, Italian National Cancer Institute "Regina Elena", Rome, Italy.
authors: Sabrina
authors: S
authors: Strano
authors: Molecular Chemoprevention Group, Italian National Cancer Institute "Regina Elena", Rome, Italy.
authors: Giovanni
authors: G
authors: Blandino
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D035683:MicroRNAs / Q000378:metabolism*; D010641:Phenotype
chemical_list: D007004:Hypoglycemic Agents; D035683:MicroRNAs; D008687:Metformin