What is the Genetic Cargo Necessary for Ferroptosis Sensitization of MCF7 Cells?

Ferroptosis is a form of programmed cell death characterized by the accumulation of reactive oxygen species, which lead to lipid peroxidation and membrane rupture. To search for novel ferroptosis inducers and inhibitors, we combined two ferroptosis inducers: erastin and RSL3 with different drug-like compounds from Pandemic Response Box, a compound library for possible Malaria treatment. We identified tipifarnib as a candidate, which was shown to be particularly effective in sensitizing MCF7 cells to ferroptosis. Aside from the known target of farnesyltransferase we believe that tipifarnib has other targets that lead to the observed phenotype. We performed a one-pot assay and identified exportin/importins as the potential targets of tipifarnib to trigger ferroptosis. We hypothesize that tipifarnib disrupts certain import/exportation of “cargos” resulting in the sensitization to ferroptosis. We treated MCF7 cells with compound inhibitors of exportin, importin, and tipifarnib. Also we shRNA to knockdown exportin, importin, to look for potential pathways that results in the phenotypic change. Through the usage of RT-PCR assays we have data that suggests possible targets and non-targets that make MCF7 cells sensitive to ferroptosis treatment. With further investigation, this provides an avenue for an alternative strategy to treating tumors.