Metformin-induced metabolic reprogramming of chemoresistant ALDH(bright) breast cancer cells

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 (ALDH(bright) cells) and their response to metformin, a promising anticancer metabolic modulator. The purified ALDH(bright) cells exhibited a different metabolic profile as compared to their chemosensitive ALDH(low) counterparts. Metformin treatment strongly affected the metabolism of the ALDH(bright) 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 ALDH(bright) and ALDH(low) cells, making the former more similar to the latter. Metformin broadly modulated microRNAs in the ALDH(bright) 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 ALDH(bright) cells and the chemosensitive ALDH(low) cells. This works adds on the potential therapeutic relevance of metformin and shows the potential for metabolic reprogramming to modulate cancer chemoresistance.