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.
Highlights
It appears increasingly clear that the stable acquisition of a cancer phenotype involves metabolic remodeling
Given the involvement of the ALDHbright cells in mediating cancer chemoresistance, we treated MCF-7, BT-474 and SUM159 cells with cisplatin and doxorubicin, two commonly used chemotherapy agents for breast cancer and we evaluated the percentage of ALDHbright cells among the surviving cell populations
Clonogenic assays with FACS-purified ALDHbright and ALDHlow cells confirmed that the ALDHbright cells in the transformed breast cancer cell lines represented the main chemoresistant cell subpopulation as compared to the ALDHlow cells (Fig. 1C-D)
Summary
It appears increasingly clear that the stable acquisition of a cancer phenotype involves metabolic remodeling. We explore which are the metabolic features of the chemoresistant ALDHbright cells and whether their metabolic characteristics reflect their functional properties This may add precious knowledge to the mechanisms of tumor relapse and its modulation, to achieve anticancer effects. With regard to this latter point, metformin, an oral anti-diabetic biguanide, has been shown to target chemoresistant putative cancer stem cells from a variety of solid tumors, including lung, prostate, ovary cancer and glioma [12,13,14]. We have shown a metabolic anticancer effect of metformin on unfractionated breast cancer cells lines which is partially dependent on DICER-mediated microRNA modulation [15]. We show that metformin treatment largely modulated the microRNA expression profile of ALDHbright cells and did so by broadly modulating microRNAs predicted to impinge on cell metabolism and to target the mentioned pathways
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