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Updated: Oct 30, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Targeting prominin2 transcription to overcome ferroptosis resistance in cancer
Caitlin W Brown1, Peter Chhoy1, Dimpi Mukhopadhyay1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
Abstract:
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.
Insights
Cancer cells resist ferroptosis via prominin2 induction. Targeting HSF1 (heat shock factor 1) with inhibitors sensitizes resistant cells to ferroptosis-inducing drugs, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ferroptosis is a regulated cell death pathway with therapeutic potential in cancer.
- Prominin2 (PROM2) is induced by ferroptosis and confers resistance.
- Targeting PROM2 induction is a strategy to overcome ferroptosis resistance.
Purpose of the Study:
- To elucidate the mechanism of PROM2 induction by ferroptosis.
- To identify novel therapeutic targets for overcoming ferroptosis resistance in cancer.
Main Methods:
- Investigated the role of 4-hydroxynonenal (4HNE) in PROM2 transcription.
- Utilized p38 MAP kinase and HSF1 (heat shock factor 1) pathway analysis.
- Tested HSF1 inhibitors in combination with ferroptosis-inducing drugs in cancer cells and mouse models.
Main Results:
- 4HNE stimulates PROM2 transcription via p38 MAP kinase-mediated activation of HSF1.
- HSF1 inhibitors sensitize diverse cancer cells to ferroptosis-inducing agents.
- Combination therapy of ferroptosis inducers and HSF1 inhibitors achieved tumor cytostasis in mice.
Conclusions:
- HSF1 is a key mediator of ferroptosis resistance through PROM2 induction.
- Inhibiting HSF1 represents a promising strategy to enhance ferroptosis-based cancer therapy.
- Combined targeting of ferroptosis and HSF1 offers a novel therapeutic approach for resistant cancers.
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