Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism

Abstract

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.

MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERα Positive Breast Cancer

“…In order to better characterize the role of miR-301a-3p in cancer stem-like cells, we assessed the expression level of miR-301a-3p by TaqMan assay in our model of cancer stem-like cells based on growing cells as mammospheres in serum-free medium supplemented with EGF and FGF [33]. We generated mammospheres from several ERα positive breast cancer cell lines (ZR-751, MCF7, T-47D and BT474) and compared miR-301a-3p level between spheres and control adherent cells.…”

“…Apart from HER2 , we observed upregulation of other markers related to cancer stem-like cells, EMT and metastatic phenotype such as CD44, ALDH1, ABCG2, VIM, ZEB1, ZEB2 and VEGFA in cells from miR-301a-3p overexpressing tumors. The cancer stem-like cell properties of miR-301a-3p overexpressing cells were further confirmed by analysis of mammospheres, the in vitro model of cancer stem-like cells [33], which expressed dramatically higher level of miR-301a-3p together with significantly lower ERα protein level, accompanied by inhibition of ERα targets GREB1 and PR. Furthermore, the other ERα-regulating miRNAs such as miR-22, -145 and -206 were not significantly and consistently elevated in sphere samples (data not shown).…”

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

“…In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [132][133][134][135][136][137][138][139][140][141][142][143][144][145]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [146][147][148][149][150].…”

Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells

“…Iron containing enzymes and haem containing enzymes play a vital role in DNA synthesis, epigenetics, cell cycles and cellular respiration, and hence cancer cells highly depend on labile Fe 2+ state iron for their growth and survival. Breast cancer cells have almost twice the storage capacity of intracellular labile Fe 2+ state iron than normal breast epithelial cells, and this is also similar in prostate and lymphoma [99,108,109]. Thus it is evident that compared to the normal cells, as cancer cells produce more H 2 O 2 and OH, they become more susceptible to Vit.C [99].…”