A Potential Novel Regulator of Ferroptosis by Cynthia Abigail Harris

Cynthia Abigail Harris

UC Berkeley | Bailey & Chris Meyer

Copper transporter CTR1 may play a role in sensitizing cells to ferroptotic cell death. CTR1 knockout and copper chelation in MEF cells is associated with increased resistance to RSL3-induced ferroptosis, suggesting a role for copper in this iron-dependent form of programmed cell death.

ABSTRACT

Ferroptosis is an iron-dependent type of cell death that results from the accumulation of reactive lipid peroxides. A recent CRISPRi screen for genes associated with sensitization to ferroptosis identified CTR1, a copper transporter, as a possible enhancer of ferroptosis. In order to validate CTR1 as a regulator of ferroptosis, MEF wild-type and CTR1 knockout cells were treated with RSL3 to induce ferroptosis; cell death was higher in the WT and could be rescued with ferrostatin-1, a ferroptosis inhibitor. This suggests that CTR1 KO cells have a greater resistance to RSL3-induced ferroptosis compared to WT. Treatment with copper chelator BCS revealed a similar phenotype to ferrostatin-1 rescue in low RSL3 conditions, but high doses of RSL3 in combination with BCS resulted in a synergistic increase in cell death in both WT and CTR1 KO MEF. Elucidating the participation of copper and potentially other redox-active metals in ferroptosis could further expand our understanding of its mechanism and allow the development of new ways to induce ferroptotic cell death in cancer and other disorders.

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