Targeting prominin2 transcription to overcome ferroptosis resistance in cancer

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.

Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

“…The increase of intracellular iron caused by NCOA4-mediated degradation of FT is involved in ferroptosis. Cells treated with GPX4 inhibitors could secrete a large number of exosomes containing FT. During ferroptosis, the level of prominin2 is negatively correlated with the level of intracellular free iron, suggesting that exosomes can protect cells from ferroptosis by expulsing intracellular iron from cells ( 29 , 30 ). Therefore, inhibition of prominin2 transcription can overcome ferroptosis resistance in cancer ( 31 ).…”

Construction and Validation of a 6-Ferroptosis Related Gene Signature for Prognosis and Immune Landscape Prediction in Melanoma

“…The prognostic role of Prominin 2 (PROM2) in human cancers is controversial. Mechanistically, reduced iron concentration in cells caused by PROM2 could protect tumors from ferroptosis, and the inhibition of PROM2 transcription sensitizes drug-resistant cancer cells to ferroptosis inducers ( Brown et al, 2021 ). Studies on AURKA and ARNTL in melanoma remain limited.…”

Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence

“…Of particular interest, novel CRISPR/Cas9-based epigenetic editing techniques could help to investigate the causative relationship between ferroptosis induction and some of the epigenetic marks [106]. When these epigenetic marks prove to be non-causal, they could alternatively be used as predictive or prognostic markers for ferroptosis sensitivity, as ferroptosis resistance has already been described in some cancer types [40,107]. Given that cancer-therapy resistance is often orchestrated by epigenetic alterations, an epigenome comparison of ferroptosis resistance and sensitivity might help to identify novel ferroptosis biomarkers and predict efficacy of ferroptosis inducers.…”