The importance of iron in the growth and progression of tumors has been widely documented. In this report, we show that tumor-initiating cells (TICs), represented by spheres derived from the MCF7 cell line, exhibit higher intracellular labile iron pool, mitochondrial iron accumulation and are more susceptible to iron chelation. TICs also show activation of the IRP/IRE system, leading to higher iron uptake and decrease in iron storage, suggesting that level of properly assembled cytosolic iron-sulfur clusters (FeS) is reduced. This finding is confirmed by lower enzymatic activity of aconitase and FeS cluster biogenesis enzymes, as well as lower levels of reduced glutathione, implying reduced FeS clusters synthesis/utilization in TICs. Importantly, we have identified specific gene signature related to iron metabolism consisting of genes regulating iron uptake, mitochondrial FeS cluster biogenesis and hypoxic response (ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 and TFRC). Principal component analysis based on this signature is able to distinguish TICs from cancer cells in vitro and also Leukemia-initiating cells (LICs) from non-LICs in the mouse model of acute promyelocytic leukemia (APL). Majority of the described changes were also recapitulated in an alternative model represented by MCF7 cells resistant to tamoxifen (TAMR) that exhibit features of TICs. Our findings point to the critical importance of redox balance and iron metabolism-related genes and proteins in the context of cancer and TICs that could be potentially used for cancer diagnostics or therapy.

• Keywords
• FeS cluster, breast cancer, iron metabolism, stem cells, tumor-initiating cells,
• MeSH
• Leukemia, Promyelocytic, Acute enzymology   genetics   MeSH
• Principal Component Analysis MeSH
• Biological Transport MeSH
• Spheroids, Cellular MeSH
• Iron Chelating Agents pharmacology   MeSH
• Drug Resistance, Neoplasm MeSH
• Phenotype MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Mitochondria enzymology   MeSH
• Mice, Transgenic MeSH
• Neoplastic Stem Cells drug effects   enzymology   pathology   MeSH
• Prostatic Neoplasms drug therapy   enzymology   genetics   pathology   MeSH
• Breast Neoplasms drug therapy   enzymology   genetics   pathology   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Gene Expression Profiling MeSH
• Tamoxifen pharmacology   MeSH
• Transcriptome * MeSH
• Dose-Response Relationship, Drug MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• Antineoplastic Agents MeSH
• Tamoxifen MeSH
• Iron MeSH