Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

• It is well accepted that intracellular iron overload that associate with various forms of cancer fuels tumormutagenesis and growth. Hence, iron chelation therapy is being increasingly used to minimize iron overload incancer patients despite significant safety and efficacy concerns. Mounting evidence suggests that estrogen (E2)downregulates hepcidin synthesis and increases serum iron concentration. It is postulated therefore that, bydownregulating hepcidin synthesis, E2 may maintain ferroportin integrity and enhance intracellular iron efflux. Here,MCF-7 and SKOV-3 cancer cells treated with increasing concentrations (5, 10 and 20 nM) of E2 were assessed forintracellular labile iron content, the expression of hepcidin, ferroportin, and transferrin receptors 1 and 2 along withcell viability at different time points post treatment. In MCF-7 cells, E2 treatment resulted in a significant reduction inhepcidin synthesis, most noticeably at the 20 nM/24 h dose, a significant increase in ferroportin expression and amarked decrease in transferrin receptors 1 and 2 expression. E2-treated cells also showed reduced intracellularlabile iron content most evidently at 20 nM/48 h dose and reduced viability especially at 20 nM/72 h dose. E2-treatedSKOV-3 showed slightly reduced intracellular labile iron content, reduced expression of hepcidin and significantlyincreased expression of TFR1 but not TFR2; FPN expression was overall similar to that of controls. The effects ofE2 on intracellular iron metabolism in SKOV-3 were most evident at 5 nM/24 h dose. These findings suggest that E2treatment induces intracellular iron efflux, which may minimize intracellular iron overload in cancer cells; disruptedexpression of transferrin receptor 1 and/or 2 may help sustain a low intracellular iron environment.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

17-β-estradiol; Hepcidin; Intracellular labile iron; Ferroportin; Transferrin receptor; MCF-7; SKOV-3

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