4.2 Article

Promotion of ferroptosis in head and neck cancer with divalent metal transporter 1 inhibition or salinomycin

Journal

HUMAN CELL
Volume 36, Issue 3, Pages 1090-1098

Publisher

SPRINGER JAPAN KK
DOI: 10.1007/s13577-023-00890-x

Keywords

Ferroptosis; Divalent metal transporter 1; Salinomycin; Iron; Lipid peroxidation

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Divalent metal transporter 1 (DMT1) inhibitors or salinomycin can induce lysosomal iron overload and selectively kill iron-addicted cancer stem cells in head and neck cancer (HNC) cells. This study revealed that DMT1 inhibition or salinomycin treatment promotes ferroptosis by increasing labile iron levels and lipid peroxidation. Silencing of DMT1 resulted in molecular changes related to iron starvation response. These findings suggest that targeting DMT1 or using salinomycin could be a novel strategy for killing iron-avid cancer cells in HNC.
Divalent metal transporter 1 (DMT1) inhibitors can selectively kill iron-addicted cancer stem cells by causing lysosomal iron overload, but their role in head and neck cancer (HNC) is unknown. We examined the role of DMT1 inhibition or salinomycin in promoting ferroptosis by lysosomal iron targeting in HNC cells. RNA interference was performed by transfection of siRNA targeting DMT1 or scrambled control siRNA in HNC cell lines. Cell death and viability, lipid peroxidation, iron contents, and molecular expression were compared between the DMT1 silencing or salinomycin group and the control. DMT1 silencing markedly accelerated cell death induced by the ferroptosis inducers. DMT1 silencing marked increases in the labile iron pool, intracellular ferrous and total iron contents, and lipid peroxidation. DMT1 silencing revealed molecular changes in iron starvation response, resulting in increases in TFRC, and decreases in FTH1. Salinomycin treatment also showed similar results to the above DMT1 silencing. DMT1 silencing or salinomycin can promote ferroptosis in HNC cells, suggesting a novel strategy for killing iron-avid cancer cells.

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