Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
Ferroptosis, a recently identified form of atypical programmed cell death, is triggered by iron-dependent accumulation of lipid peroxides. Because cancer cells contain higher concentrations of iron than normal cells, ferroptosis is considered as an effective approach to eliminate cancer cells specifically. However, there are no anti-cancer drugs that induce ferroptosis. In this study, we screened novel ferroptosis inducers from among existing drugs, and found that polymyxin B (PMB), a polypeptide antibiotic agent, can induce ferroptosis in cancer cell lines. Mechanistically, PMB induced ferroptosis by increasing intracellular free iron through ferritinophagy, a type of autophagy that specifically degrades the intracellular iron-storage protein ferritin. Moreover, it turned out that PMB upregulates the expression of NCOA4, an inducer of ferritinophagy. Interestingly, PMB translationally upregulated the NCOA4 expression under iron-rich conditions, even though, in general, NCOA4 is upregulated in a transcription-dependent manner when iron is depleted. Together, these findings suggest that PMB induces ferritinophagy-dependent ferroptosis by targeting NCOA4, and works as an inducer of ferroptosis. Considering that PMB is an already-approved drug, our study raised the possibility that PMB can be applied to an anti-cancer drug through drug repositioning approaches.
