Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences
Cancer Biology | Neoplasms
Understanding how cancer cells resist ferroptosis is a significant problem that impacts ongoing efforts to stimulate ferroptosis as a therapeutic strategy. We reported that prominin2 is induced by ferroptotic stimuli and functions to resist ferroptotic death. Although this finding has significant implications for therapy, specific prominin2 inhibitors are not available. We rationalized that the mechanism by which prominin2 expression is induced by ferroptotic stress could be targeted, expanding the range of options to overcome ferroptosis resistance. Here, we show that that 4-hydroxynonenal (4HNE), a specific lipid metabolite formed from the products of lipid peroxidation stimulates PROM2 transcription by a mechanism that involves p38 MAP kinase-mediated activation of HSF1 and HSF1-dependent transcription of PROM2. HSF1 inhibitors sensitize a wide variety of resistant cancer cells to drugs that induce ferroptosis. Importantly, the combination of a ferroptosis-inducing drug and an HSF1 inhibitor causes the cytostasis of established tumors in mice, although neither treatment alone is effective. These data reveal a novel approach for the therapeutic induction of ferroptosis in cancer.
cancer, ferroptosis, heat shock factor 1, prominin2, therapy
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Copyright 2021 The Authors. Published under the terms of the CC BY 4.0 license. License: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
Brown CW, Chhoy P, Mukhopadhyay D, Karner ER, Mercurio AM. Targeting prominin2 transcription to overcome ferroptosis resistance in cancer. EMBO Mol Med. 2021 Aug 9;13(8):e13792. doi: 10.15252/emmm.202013792. Epub 2021 Jul 5. PMID: 34223704; PMCID: PMC8350900. Link to article on publisher's site
EMBO molecular medicine
Brown CW, Chhoy P, Mukhopadhyay D, Karner ER, Mercurio AM. (2021). Targeting prominin2 transcription to overcome ferroptosis resistance in cancer. Open Access Publications by UMass Chan Authors. https://doi.org/10.15252/emmm.202013792. Retrieved from https://escholarship.umassmed.edu/oapubs/4834
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.